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International Journal of
Molecular Sciences
Review
Recent Advances in Developing Small Molecules
Targeting Nucleic Acid
Maolin Wang 1,2,3 , Yuanyuan Yu 1,2,3 , Chao Liang 1,2,3 , Aiping Lu 1,2,3, * and Ge Zhang 1,2,3, *
1
2
3
*
Institute of Integrated Bioinfomedicine and Translational Science (IBTS), School of Chinese Medicine,
Hong Kong Baptist University, Hong Kong 999077, China; [email protected] (M.W.);
[email protected] (Y.Y.); [email protected] (C.L.)
Shenzhen Lab of Combinatorial Compounds and Targeted Drug Delivery, HKBU Institute of Research and
Continuing Education, Shenzhen 518000, China
Institute for Advancing Translational Medicine in Bone and Joint Diseases, School of Chinese Medicine,
Hong Kong Baptist University, Hong Kong 999077, China
Correspondence: [email protected] (A.L.); [email protected] (G.Z.);
Tel.: +852-3411-2456 (A.L.); +852-3411-2958 (G.Z.)
Academic Editor: Mateus Webba da Silva
Received: 2 March 2016; Accepted: 9 May 2016; Published: 30 May 2016
Abstract: Nucleic acids participate in a large number of biological processes. However, current
approaches for small molecules targeting protein are incompatible with nucleic acids. On the other
hand, the lack of crystallization of nucleic acid is the limiting factor for nucleic acid drug design.
Because of the improvements in crystallization in recent years, a great many structures of nucleic
acids have been reported, providing basic information for nucleic acid drug discovery. This review
focuses on the discovery and development of small molecules targeting nucleic acids.
Keywords: nucleic acids; nucleic acids targeting; small molecules; DNA drug discovery; RNA
drug discovery
1. Introduction
Nucleic acids play significant roles in variety kinds of biological processes [1–5]. According to
the differences on sugar scaffold, nucleic acids can be classified into two categories. DNAs and
RNAs participate in gene storage, replication, transcription and other important biological activities.
Thus, targeting nucleic acids can regulate a large range of biological processes, especially genetic
diseases. Nucleic acids play significant roles in anticancer [6] and antiviral [7] processes. Therefore, the
small molecules targeting nucleic acids are desirable and have become a topic issue in recent years.
However, small molecules targeting nucleic acids are more difficult to discover than targeting
protein, which result from various reasons. Nucleic acid lacks spatial structure information from X-ray
crystallization, nuclear magnetic resonance (NMR) or other imaging methods. Current approaches for
small molecules targeting protein are incompatible with nucleic acids. Most of the docking methods,
for example, do not regard RNA and DNA receptors as flexible bodies [8–10], which constrains the
conformational changes of nucleic acids. Fortunately, the areas of structural biology and computational
chemistry have improved dramatically. A large number of structures of nucleic acids have been
reported. Several computational methods and force fields have been developed and modified [11,12].
These improvements provide a new horizon to discovery and design novel small molecules targeting
nucleic acids.
Depending on the differences on sugar scaffold of nucleic acids, small molecules targeting nucleic
acids can be separated into two main categories: small molecules targeting DNA and small molecules
targeting RNA (in which DNA and RNA can form different conformations). This review focuses on
the recent discovery and development of small molecules targeting DNA and RNA.
Int. J. Mol. Sci. 2016, 17, 779; doi:10.3390/ijms17060779
www.mdpi.com/journal/ijms
Int. J. Mol. Sci. 2016, 17, 779
2. Small
Targeting
DNA
Int. J. Molecules
Mol. Sci. 2016, 17,
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2. Small
Molecules
Targeting
2.1. Small
Molecules
Targeting
DNADNA
Duplex
2. Small Molecules Targeting DNA
Small
MoleculesForming
Targeting DNA
Duplex
2.1.1. 2.1.
Small
Molecules
Covalent
Bonds with DNA Duplex
2.1. Small Molecules Targeting DNA Duplex
Psoralen
orMolecules
psoraleneForming
has been
used as
mutagen
to treat
skin diseases including psoriasis and
2.1.1. Small
Covalent
Bonds
with DNA
Duplex
vitiligo.
Psoralen
interacts Forming
with standard
DNA duplex,
through
the 5,6 double bond in pyrimidine ring,
2.1.1.
Small Molecules
Covalent
with DNA
Duplex
Psoralen
or psoralene has been
usedBonds
as mutagen
to treat
skin diseases
including psoriasis and
1 -(Hydroxymethyl)-4,5
1 ,8-trimethylpsoralen,
whichvitiligo.
can stop
replication
and
transcription.
4
short for
Psoralen
interacts
with
standard
DNA
duplex,
through
the
5,6
double
bond in
pyrimidine
Psoralen or psoralene has been used as mutagen to treat skin diseases including
psoriasis
and
HMT,ring,
has reasonable
solubility
and
DNA
binding
affinity,
as double
shownbond
in Figure
1A. Figure 2B
which
can water
stop replication
and high
transcription.
4′-(Hydroxymethyl)-4,5′,8-trimethylpsoralen,
vitiligo.
Psoralen
interacts
with standard
DNA
duplex,
through
the 5,6
in pyrimidine
showsshort
the
crystal
structure
of
a
short
DNA
complex
with
HMT
reported
by
Spielmann
et in
al. [13].
for
HMT,
has
reasonable
water
solubility
and
high
DNA
binding
affinity,
as
shown
ring, which can stop replication and transcription. 4′-(Hydroxymethyl)-4,5′,8-trimethylpsoralen,
The HMT
structure
crosses
both
the
minor
and
major
grooves
through
the
5,6
double
bonds
of
Figure
1A.
Figure
2B
shows
the
crystal
structure
of
a
short
DNA
complex
with
HMT
reported
by
short for HMT, has reasonable water solubility and high DNA binding affinity, as shown in
Spielmann
et
al.
[13].
The
HMT
structure
crosses
both
the
minor
and
major
grooves
through
the
5,6
Figure ring
1A. Figure
2B thymines.
shows the crystal
of a short
DNAinteractions
complex with
HMT
by
pyrimidine
and two
There structure
are apparent
stacking
from
thereported
ring system
of
ofnearby.
pyrimidine
ring
and
twocrosses
thymines.
There
areand
apparent
stacking
interactions
from
Spielmann
et al.
[13].
TheThe
HMT
structure
bothof
the
minor
and
major
grooves
through
the
5,6 rings
HMT double
and thebonds
bases
high
binding
affinity
HMT
duplex
results
from
aromatic
the
ringbonds
systemofofpyrimidine
HMT
and the
nearby.
The
high
binding
affinity of
HMT
duplex
double
ringbases
andThe
two
thymines.
There
arecomplex
apparent
stacking
interactions
from the
stacking
and
hydrophobic
interactions.
crystal
study
of
the
of
DNAand
and
HMT results
showed
from
aromatic
rings
stacking
and
hydrophobic
interactions.
The
crystal
study
of
the
complex
DNA
the ring system of HMT and the bases nearby. The high binding affinity of HMT and duplexofresults
Holliday junction was formed in the adduct of DNA-HMT. The interaction between DNA and HMT
and
showed
Holliday
was formed
in theThe
adduct
ofstudy
DNA-HMT.
The interaction
fromHMT
aromatic
ringsthe
stacking
andjunction
hydrophobic
interactions.
crystal
of the complex
of DNA
is related
withDNA
sequence,
which
may play
a role in repairing
the
psoralen
damage
in chemotherapy
between
and
HMT
is
related
with
sequence,
which
may
play
a
role
in
repairing
psoralen
and HMT showed the Holliday junction was formed in the adduct of DNA-HMT. Thethe
interaction
treatment.
The
conformation
of
DNA is
extremely
twisted
at the
of thymine
connected
damage
in
chemotherapy
treatment.
The
conformation
of may
DNA
isbases
extremely
at the
the psoralen
baseswith
of the
between
DNA
and HMT is
related
with
sequence,
which
play
a role
in twisted
repairing
hexatomic
pyrone
of
the
molecule.
thymine
connected
with
the
hexatomic
pyrone
of
the
molecule.
damage in chemotherapy treatment. The conformation of DNA is extremely twisted at the bases of
thymine connected with the hexatomic pyrone of the molecule.
Figure 1. (A) Chemical structure of HMT; and (B) NMR structure of a short DNA complex with HMT
Figure 1. (A) Chemical structure of HMT; and (B) NMR structure of a short DNA complex with HMT
(RCSB
Data Bank
(PDB) code:
204D).
structureofrepresents
the small
molecule.
The
Figure Protein
1. (A) Chemical
structure
of HMT;
andThe
(B)orange
NMR structure
a short DNA
complex
with HMT
(RCSBpurple
Protein
Data Bank
(PDB)
code:
204D).
The orange
structure
represents
the
small molecule.
structure
represents
the code:
backbone
ofThe
nucleic
acid;
the blue
and red the
atoms
inmolecule.
the molecule
(RCSB Protein
Data
Bank (PDB)
204D).
orange
structure
represents
small
The
The purple
structure
the backbone
of nucleic acid; the blue and red atoms in the molecule
represent
nitrogenrepresents
and oxygen
respectively.
purple structure
represents
theatoms,
backbone
of nucleic acid; the blue and red atoms in the molecule
represent
nitrogen
andand
oxygen
atoms,
respectively.
represent
nitrogen
oxygen
atoms,
respectively.
Figure 2. (A) Chemical structure of Aflatoxin B1 adduct; and (B) NMR structure of a DNA duplex
complex
Aflatoxinstructure
B1 adduct
(PDB code:
structure
represents
theduplex
small
Figure 2. with
(A) Chemical
of Aflatoxin
B12KH3).
adduct;The
andorange
(B) NMR
structure
of a DNA
Figure 2. (A) Chemical structure of Aflatoxin B1 adduct; and (B) NMR structure of a DNA duplex
molecule;
the purple
structure
represents
backbone
nucleic
acid;structure
the blue represents
and red atoms
the
complex with
Aflatoxin
B1 adduct
(PDBthe
code:
2KH3).ofThe
orange
the in
small
complex
with Aflatoxin
B1 adduct
(PDB atoms,
code: respectively.
2KH3). The orange structure represents the small
molecule
and
oxygen
molecule;represent
the purplenitrogen
structure
represents
the backbone of nucleic acid; the blue and red atoms in the
molecule;
the purple structure represents the backbone of nucleic acid; the blue and red atoms in the
molecule represent nitrogen and oxygen atoms, respectively.
molecule represent nitrogen and oxygen atoms, respectively.
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Aflatoxin B1 (AFB) is a common contaminant in a variety of foods including peanuts, cottonseed
meal, corn,
and other
grains
well as animal
feeds.inAflatoxin
B1foods
is considered
most toxic
aflatoxin
Aflatoxin
B1 (AFB)
is aascommon
contaminant
a variety of
includingthe
peanuts,
cottonseed
andmeal,
it is highly
implicated
in hepatocellular
carcinoma
(HCC)
in humans
[14]. The epoxide
metabolite
corn, and
other grains
as well as animal
feeds.
Aflatoxin
B1 is considered
the most
toxic
of AFB
can react
duplex
DNA to
a cationic
adduct
(Figure
2A). An[14].
NMR
aflatoxin
and itwith
is highly
implicated
inproduce
hepatocellular
carcinoma
(HCC)
in humans
Thestructure
epoxide of
AFB resolved
can react and
withreported
duplex DNA
to produce
cationicinadduct
2A).
An structure
NMR
thismetabolite
adduct hasofbeen
by Stone
[15], asashown
Figure(Figure
2B. This
NMR
structure
of
this
adduct
has
been
resolved
and
reported
by
Stone
[15],
as
shown
in
Figure
2B.
This
shows that Aflatoxin B1 substructure inserts into DNA duplex strand. The adduct acts as a covalent
NMR
structure
shows that
B1 substructure
inserts
into DNA
duplex strand.
adduct
binder,
which
can crosslink
to Aflatoxin
duplex DNA
conformation
inducing
the modification
andThe
change
in the
acts
as
a
covalent
binder,
which
can
crosslink
to
duplex
DNA
conformation
inducing
the
modification
DNA conformation. The changed DNA will stop interacting with related proteins, which can block
change in the DNA conformation. The changed DNA will stop interacting with related proteins,
the and
process
of replication or transcription.
which can block the process of replication or transcription.
Another DNA duplex adduct, a synthetic N44C–ethyl–N44 C (Figure 3A), was discovered to interact
Another DNA duplex adduct, a synthetic N C–ethyl–N C (Figure 3A), was discovered to interact
with DNA by Miller [16]. The DNA study indicated that the ethyl cross-linked the base pairs in
with DNA by Miller [16]. The DNA study indicated that the ethyl cross-linked the base pairs in the
the structure
structuresolution.
solution.However,
However,
the ethyl linker does not remarkably change the B-form DNA
the ethyl linker does not remarkably change the B-form DNA
conformation
[17],
as
shown
in
Figure
conformation [17], as shown in Figure3B.
3B.
Figure 3. (A) Chemical structure of N4C–ethyl–N4C adduct; and (B) one strand of NMR structure of a
4 C adduct; and (B) one strand of NMR structure
Figure 3. (A) Chemical structure 4of N4 C–ethyl–N
4C adduct (PDB code: 2OKS). The orange structure
DNA duplex complex with N C–ethyl–N
4
4
of a DNA duplex complex with N C–ethyl–N C adduct (PDB code: 2OKS). The orange structure
represents the small molecule; the purple structure represents the backbone of nucleic acid; the blue
represents
small
molecule;
purplenitrogen
structure
represents
the backbone
of nucleic acid; the blue
and red the
atoms
in the
moleculethe
represent
and
oxygen atoms,
respectively.
and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
Similar interactions were reported in the trimethylene related structures (Figure 4A) and DNA
duplex
conformation
Two
DNA duplexes
structures were
resolved
and submitted
to Protein
Similar
interactions[18].
were
reported
in the trimethylene
related
structures
(Figure 4A)
and DNA
Data
Bank.
Although
the
stacking
between
the
linked
bases
and
neighbor
bases
was
different,
duplex conformation [18]. Two DNA duplexes structures were resolved and submitted to both
Protein
ofBank.
the two
structuresthe
indicated
that
the duplexes
couldbases
maintain
hydrogen
bonds
the B-form
Data
Although
stacking
between
the linked
and the
neighbor
bases
wasand
different,
both of
geometry (Figure 4B,C).
the two structures indicated that the duplexes could maintain the hydrogen bonds and the B-form
Mitomycin C (Figure 5A) is a member of mitomycins, which contains aziridine substructure and
geometry (Figure 4B,C).
are extracted from natural products isolated from streptomycetes. The molecule is used as
Mitomycin C (Figure 5A) is a member of mitomycins, which contains aziridine substructure
a chemotherapy drug for cancer. Mitomycin C alkylates the guanine in C–G base pairs of the DNA
andconformation
are extracted[19].
from
natural products isolated from streptomycetes. The molecule is used as
The crystal complex of a short DNA with mitomycin C was reported by
a chemotherapy
drug
for
cancer.
Mitomycin
C alkylates
the guanine
in C–G
pairs
of the
Patel et al. [20]. Unlike other
standard
DNA duplexes,
the mitomycin
alkylated
DNAbase
duplex
shows
DNA
conformation
[19]. The
of a short
DNA
mitomycin
reported
A-form
base pair stacking
andcrystal
B-formcomplex
sugar puckers.
The ring
of with
mitomycin
locatesCinwas
the minor
by Patel
et al.
[20].
standard forms
DNA aduplexes,
mitomycin
alkylated
DNA5B.
duplex shows
groove.
And
theUnlike
ring of other
indoloquinone
45° to thethe
helix
axis, as shown
in Figure
A-form As
base
pair stacking
B-form
sugar
Thechange
ring ofthe
mitomycin
locates in the
minor
mentioned,
theseand
small
molecules
canpuckers.
modify and
overall conformation
of the
˝
conformation
by cross-linking
to DNA
duplexes.
changed
conformations
will stop
groove.
And the ring
of indoloquinone
forms
a 45 toThe
the helix
axis,DNA
as shown
in Figure 5B.
interacting
with thethese
corresponding
biologicalcan
partners,
thus
thechange
transcription
or replication
process of
As mentioned,
small molecules
modify
and
the overall
conformation
be blocked. by
Thiscross-linking
is how this kind
of molecules
works
in the
chemotherapeutics
treatment. These
the will
conformation
to DNA
duplexes.
The
changed
DNA conformations
will stop
molecules
showed
high
toxicity
in
normal
cells,
just
because
of
its
low
selectivity.
To
decrease
interacting with the corresponding biological partners, thus the transcription or replication process
and promote
the comprehension
the interaction
mechanism betweentreatment.
DNA
willresistance
be blocked.
This is selectivity,
how this kind
of molecules of
works
in the chemotherapeutics
and drugs will be of significant importance.
These molecules showed high toxicity in normal cells, just because of its low selectivity. To decrease
resistance and promote selectivity, the comprehension of the interaction mechanism between DNA
and drugs will be of significant importance.
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Figure 4. (A) Chemical structure of N2G–trimethylene–N2G; (B) crystal complex of a DNA with N2G–
Figure 4. (A) Chemical
structure of N2 G–trimethylene–N2 G; (B) crystal complex of a DNA with
trimethylene–N2G cross-link (PDB code: 2KNK); and (C) crystal complex of a DNA with N2G–
2
2
N G–trimethylene–N
G structure
cross-link
(PDB
code: 2KNK);2G;
and
(C)
crystal
complex
of a DNA
with
Figure 4. (A) Chemical
ofcode:
N2G–trimethylene–N
(B)
crystal
complex
ofthe
a DNA
N2G–
2G cross-link
trimethylene–N
(PDB
2KNL). The orange
structure
represents
smallwith
molecule;
2 G cross-link (PDB code: 2KNL). The orange structure represents the 2small
2G cross-link
N2 G–trimethylene–N
trimethylene–N
(PDB
code:
2KNK);
and
(C)
crystal
complex
of
a
DNA
with
N
G–
the purple structure represents the backbone of nucleic acid; the blue and red atoms in the molecule
2G cross-link
molecule;
thenitrogen
purple
structure
represents
the backbone
of nucleic
acid;
the blue the
andsmall
red atoms
in the
trimethylene–N
(PDB
code:
2KNL).
The orange
structure
represents
molecule;
represent
and
oxygen
atoms,
respectively.
the purple
structure
represents
the backbone
nucleic acid; the blue and red atoms in the molecule
molecule
represent
nitrogen
and oxygen
atoms,ofrespectively.
represent nitrogen and oxygen atoms, respectively.
Figure 5. (A) Chemical structure of mitomycin C; and (B) crystal complex of a short DNA with
mitomycin C (PDB code: 199D). The orange structure represents the small molecule; the purple
Figure 5.represents
Chemical
structure of
ofnucleic
mitomycin
C; and (B) crystal complex of a short DNA with
structure
thestructure
backbone
acid. C;
Figure
5. (A)(A)
Chemical
mitomycin
and (B) crystal complex of a short DNA with
mitomycin C (PDB code: 199D). The orange structure represents the small molecule; the purple
mitomycin C (PDB code: 199D). The orange structure represents the small molecule; the purple
representsTargeting
the backbone
of DNA
nucleicDuplex
acid. in Minor Groove
2.1.2.structure
Small Molecules
with
structure represents the backbone of nucleic acid.
affect
the gene Targeting
expression,
the DNA
smallDuplex
molecules
can not
only insert into the DNA strand, but
2.1.2.To
Small
Molecules
with
in Minor
Groove
2.1.2.
Targeting
DNAofDuplex
in Minor
Groove
alsoSmall
bind Molecules
to the major
or minorwith
grooves
high binding
affinity.
For minor groove, typical small
To affect
the
gene expression,
the
small
molecules
can not netropsin,
only insertberenil,
into theand
DNA
strand, but
molecules
are
heterocylic
dications
and
polyamides,
including
pentamidine,
To bind
affectto
the
gene
expression,
the
small
molecules
canaffinity.
not onlyFor
insert
into
the DNA
strand,
also
the
major
or
minor
grooves
of
high
binding
minor
groove,
typical
smallbut
as shown in Figure 6. Originally, these molecules were found to bind AT-rich areas preferentially.
alsomolecules
bind to the major
or minor
grooves
of high binding
affinity.
For minor
groove,
typical small
heterocylic
dications
polyamides,
including
netropsin,
berenil,
and
pentamidine,
Then, theseare
molecules
appeared
nearand
G–C
and C–G base
pairs [21,22].
The molecules
targeting
minor
molecules
are
heterocylic
dications
and
polyamides,
including
netropsin,
berenil,
and
pentamidine,
as shown
in Figure
6. Originally,
theseofmolecules
were
found
to bindanti-tumor
AT-rich areas
groove
have
been studied
as a series
therapeutics
with
anti-viral,
and preferentially.
anti-bacterial
as shown
in Figure
6. Originally,
these
molecules
found
to bind
areas
preferentially.
Then, these
molecules
appeared near
G–C
and C–G were
base pairs
[21,22].
TheAT-rich
molecules
targeting
minor
Then,
thesehave
molecules
appeared
G–C
C–G base
pairs
[21,22]. anti-tumor
The molecules
minor
groove
been studied
as anear
series
of and
therapeutics
with
anti-viral,
and targeting
anti-bacterial
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groove have been studied as a series of therapeutics with anti-viral, anti-tumor and anti-bacterial
activities[23–25].
[23–25].Some
Somestructural
structuralstudies
studieshave
havebeen
beeninvestigated
investigatedas
asthe
thebasis
basisof
ofthe
thedesign
designof
of small
small
activities
activities [23–25]. Some structural studies have been investigated as the basis of the design of small
molecules[26–30].
[26–30].The
The
crystal
complex
of DNA
duplex
Hoechst
33528
is shown
in Figure
molecules
crystal
complex
of DNA
duplex
andand
Hoechst
33528
is shown
in Figure
7. The7.
molecules [26–30]. The crystal complex of DNA duplex and Hoechst 33528 is shown in Figure 7. The
The
Hoechst
33528
is
clamped
in
the
minor
groove
of
the
DNA
structure.
Hoechst 33528 is clamped in the minor groove of the DNA structure.
Hoechst 33528 is clamped in the minor groove of the DNA structure.
Figure
of small
molecules for
DNA minor
groove.
Figure6.6.
6.Typical
Typicalstructures
structures
Figure
Typical
structures of
of small
small molecules
molecules for
for DNA
DNA minor
minor groove.
groove.
Figure 7. Crystal complex of DNA duplex and Hoechst 33528 (PDB code: 8BNA). The orange structure
Figure 7.
7. Crystal
complex
of
duplex
and
33528
code:
The
structure
Figure
Crystal
complex
of DNA
DNA
duplex structure
and Hoechst
Hoechst
33528 (PDB
(PDB
code: 8BNA).
8BNA).
The orange
orange
represents
the small
molecule;
the purple
represents
the backbone
of nucleic
acid; structure
the blue
represents
the
small
molecule;
the
purple
structure
represents
the
backbone
of
nucleic
acid;
the blue
blue
represents the small molecule; the purple structure represents the backbone of nucleic acid; the
and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
and
red
atoms
in
the
molecule
represent
nitrogen
and
oxygen
atoms,
respectively.
and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
Except for the drug-like molecules, some unusual compounds were also identified to locate in
Except for the drug-like molecules, some unusual compounds were also identified to locate in
Except
for the
some unusual
compounds
were that
also itidentified
in
the minor
groove
ofdrug-like
DNA. Anmolecules,
8 ring molecule
(Figure 8A)
was reported
can bindto
tolocate
a DNA
the minor groove of DNA. An 8 ring molecule (Figure 8A) was reported that it can bind to a DNA
the minor
groove
of DNA. structure
An 8 ring indicates
molecule that
(Figure
wasconformation
reported thathas
it can
bind
to a DNA
duplex
[31].
The resolved
the 8A)
DNA
been
remarkably
duplex [31]. The resolved structure indicates that the DNA conformation has been remarkably
duplex [31].
resolved
structure
indicates
thatand
the the
DNA
conformation
has
been
remarkably
changed.
changed.
TheThe
minor
groove
has been
widened,
major
groove has
been
narrowed.
The
minor
changed. The minor groove has been widened, and the major groove has been narrowed. The minor
The
minor
groove
has
been
widened,
and
the
major
groove
has
been
narrowed.
The
minor
and
major
and major grooves are both approximate 4 Å (Figure 8B). Additionally, the helix center direction
and major grooves are both approximate 4 Å (Figure 8B). Additionally, the helix center direction
aremore
both approximate
Å (Figure
8B). Additionally,
the helix
center
twisted more
isgrooves
twisted
than 18° to 4the
major groove,
in comparison
with
thedirection
inherentiscounterparts.
is twisted
more than 18° to the major groove, in comparison with the inherent counterparts.
˝ to the
than
18
major
groove,
in
comparison
with
the
inherent
counterparts.
The
distortion
provides
The distortion provides a fundamental element for supporting the concept of allosteric change
of the
The distortion provides a fundamental element for supporting the concept of allosteric change of the
a
fundamental
element
for
supporting
the
concept
of
allosteric
change
of
the
DNA
conformation
with
DNA conformation with inhibitors locating in minor grooves.
DNA conformation with inhibitors locating in minor grooves.
inhibitors locating in minor grooves.
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
6 of 24
6 of 23
Figure 8. (A) Chemical structure of 8 ringmolecule; and (B) complex of a DNA with 8 ring
Figure 8. (A) Chemical structure of 8 ringmolecule; and (B) complex of a DNA with 8 ring molecule (PDB
molecule (PDB code: 3I5L). The blue and red atoms in the molecule represent nitrogen and oxygen
code: 3I5L). The blue and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
atoms, respectively.
small
molecules
can
bindtotononstandard
nonstandard DNA
DNA duplex
duplex as
base
pairs
may
TheThe
small
molecules
can
bind
aswell.
well.Hoogsteen
Hoogsteen
base
pairs
may
occur
in alternating
A–T
sequences,
which
abundantinineukaryotic
eukaryoticanimals.
animals. Because
Because of
occur
in alternating
A–T
sequences,
which
areare
abundant
of the
the lack
lack of
of structural
information,
however,
little analysis
in this
field. Recently,
the complex
of
structural
information,
however,
there isthere
little is
analysis
in this field.
Recently,
the complex
of Hoogsteen
Hoogsteen
DNA
duplex
and
pentamidine
(Figure
9A)
was
determined
and
reported
[32].
The
X-ray
DNA duplex and pentamidine (Figure 9A) was determined and reported [32]. The X-ray DNA structure
DNAa structure
a mixture
Watson–Crick
and(Figure
Hoogsteen
patternprevious
(Figure minor
9B). Unlike
presents
mixture ofpresents
Watson–Crick
andofHoogsteen
pattern
9B). Unlike
binders,
previous minor binders, pentamidine does not bind to the minor groove totally. Only the center of
pentamidine does not bind to the minor groove totally. Only the center of the pentamidine is bound to
the pentamidine is bound to the minor groove, leaving the positively charged ends detached from
the minor groove, leaving the positively charged ends detached from the DNA and free to interact
the DNA and free to interact with phosphate groups from adjacent duplexes in the crystal. This new
with phosphate groups from adjacent duplexes in the crystal. This new binding pattern has potent
binding pattern has potent inspiration for antibacterial design of pentamidine.
inspiration for antibacterial design of pentamidine.
Figure 9. (A) Chemical structure of pentamidine; and (B) complex of DNA with pentamidine (PDB
code:
3EY0).
The
orange structure
structureofrepresents
theand
small
purple
structure represents
Figure
9. (A)
Chemical
pentamidine;
(B) molecule;
complex ofthe
DNA
with pentamidine
(PDB
the backbone
of
nucleic
acid;
the
blue
and
red
atoms
in
the
molecule
represent
nitrogen
and oxygen
code: 3EY0). The orange structure represents the small molecule; the purple structure represents
the
atoms,
respectively.
backbone
of nucleic acid; the blue and red atoms in the molecule represent nitrogen and oxygen atoms,
respectively.
Int. J. Mol. Sci. 2016, 17, 779
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Int. J. Mol. Sci. 2016, 17, 779
7 of 23
2.1.3. Small Molecules Targeting with DNA Duplex in Major Groove
2.1.3. Small Molecules Targeting with DNA Duplex in Major Groove
For major groove studies, there are less reports of small molecule targeting information. Due to
For major groove studies, there are less reports of small molecule targeting information. Due to
the requirement
of larger compounds, few complexes of molecules and DNA major grooves are
the requirement of larger compounds, few complexes of molecules and DNA major grooves are
determined. Although majority of carbohydrates bind to the DNA minor grooves, some of them can
determined. Although majority of carbohydrates bind to the DNA minor grooves, some of them can
showshow
binding
affinity to DNA major groove. The reason for this major groove binding is the large size
binding affinity to DNA major groove. The reason for this major groove binding is the large
of carbohydrates
and theirand
hydrophilic
and hydrophobic
substructures.
Some
classic
major
groove
size of carbohydrates
their hydrophilic
and hydrophobic
substructures.
Some
classic
major
binders
are listed
inare
Figure
groove
binders
listed10
in [33].
Figure 10 [33].
Figure 10. Typical structures of small molecules for DNA major groove. (A) The structure of
Figure 10. Typical structures of small molecules for DNA major groove. (A) The structure of
neomycin-grove binder; (B) The structure of nogalamycin; (C) The structure of neocarzinostatin.
neomycin-grove binder; (B) The structure of nogalamycin; (C) The structure of neocarzinostatin.
Neocarzinostatin and related derivatives have been used as anti-tumor agents for decades [34,35].
This kind of molecule
can form
a complex
damageagents
DNAfor
bydecades
hydrogen
Neocarzinostatin
and related
derivatives
have with
been protein
used as and
anti-tumor
[34,35].
abstraction
[36]. Incan
order
to aunderstand
the mechanism
interaction
DNA duplex
and [36].
This kind
of molecule
form
complex with
protein andand
damage
DNAbetween
by hydrogen
abstraction
molecule,
the complex
the DNA duplex
and neocarzinostatin
wereduplex
reported.
In order
to understand
the of
mechanism
and interaction
between DNA
andNeocarzinostatin-gb
molecule, the complex
and neocarzinostatin-glu were used as ligand to bind to the DNA duplex. As shown in Figure 11,
of the DNA duplex and neocarzinostatin were reported. Neocarzinostatin-gb and neocarzinostatin-glu
both of the two complex structures are observed [37,38]. The majority of the neocarzinostatin-gb
were used as ligand to bind to the DNA duplex. As shown in Figure 11, both of the two complex
binds to the major groove. The two rings of the molecule are close to each other in the structure.
structures
are observed
[37,38]. The majority
of the
neocarzinostatin-gb
binds
major
groove.
However,
the neocarzinostatin-glu
binds to the
minor
groove. The differences
of to
thethe
two
binding
The two
rings
of
the
molecule
are
close
to
each
other
in
the
structure.
However,
the
neocarzinostatin-glu
modes provide significant inspiration into small molecule-DNA specific targeting.
binds to the minor groove. The differences of the two binding modes provide significant inspiration
into small molecule-DNA specific targeting.
Figure 11. Cont.
Figure 11. Cont.
Int. J. Mol. Sci. 2016, 17, 779
8 of 24
Figure 11. (A) Chemical structure of neocarzinostatin-gb; (B) complex of a DNA with neocarzinostatin-gb
(PDB code: 1KVH); (C) chemical structure of neocarzinostatin-glu; and (D) complex of DNA with
neocarzinostatin-glu (PDB code: 1MP7). The orange structure represents the small molecule; the purple
structure represents the backbone of nucleic acid; the blue and red atoms in the molecule represent
nitrogen and oxygen atoms, respectively.
2.1.4. Small Molecules Intercalating into DNA Duplex
Inserting a molecule between the base pairs of DNA is another binding pattern of small molecules
targeting DNA duplexes. Inserting to the base pairs can interrupt DNA replication and transcription.
The insertion results from hydrophobic, hydrogen bonding and van der Waals forces [39]. The insertion
lengthens the length of DNA and reduces the helical twist [40,41]. In previous study, only molecules
with fused ring systems were found to insert into the base pairs of DNA duplexes. Later, molecules with
electrophilic or cationic groups behaved the same insertion pattern. However, the ring systems were
not required [42,43]. Various compounds have been identified as intercalators, including ditercalinium,
dactinomycin, daunomycin and adriamycine. Intercalators can be used as anti-fungal, anti-tumor, and
anti-neoplastic agents. However, due to the toxicity, most of the compounds were failed during the
1
clinical trial [44].
Daunomycin (trade name Cerubidine) is used to treat various cancers as chemotherapy drug [45].
Specifically, the most common use is treating some types of leukemia. Daunomycin (Figure 12A)
consists of a planar ring, an amino sugar structure and a fused cyclohexane ring system. A lot
of structural studies have been investigated to understand the interaction between DNA duplex
and molecule [28,46–51]. Most of the structures indicate that two daunomycin molecules insert
into the G–C steps with the sugar moiety in duplex, as shown in Figure 12B. Through sequence
selectivity investigation by different biophysical methods, it was revealed that this ligand prefers
a purine-pyrimidine step and the DNA duplexes are usually elongated or twisted after binding to the
small molecule.
Adriamycin (Figure 12C) contains an extra hydroxyl group, compared to daunomycin. Although, the
daunomycin and adriamyc in have nearly the same structure, their functions are remarkably diverse.
Adriamycin is used to treat the tumor, while daunomycin is an effective drug in leukemias [47].
The complex structures of DNA duplex and compounds have been determined. In order to understand
the differences between the two compounds, the complexes of the two molecules with a same DNA
were resolved. The two complex structures showed a little differences between each other. Moreover,
the hydroxyl group of the adriamycin interacts with a water molecule in the complex (Figure 12D).
Ditercalinium, as shown in Figure 13A, is regarded as a DNA intercalator in treatment of cancer.
The structure of ditercalinium is a dimer of pyridocarbozole. Thus, the molecule can bind to DNA
duplex by bis-intercalation and then induce DNA repair in eukaryotic or prokaryotic cell [52–54].
Afterwards, pyridocarbozole derivatives and related bioactivity have been studied [55–57]. The structure
of DNA duplex and ditercalinium showed that the dimer of the molecule inserted to two G–C steps
of the conformation (Figure 13B). The duplex of the DNA maintains a right-handed helix and has
a binding site in major groove. The nitrogens with positive charge of the molecule make the charge
interaction toward major groove of DNA [58]. In the complex structure, the helix is twisted at
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
approximate 15˝ to minor
9 of 24
9 of 23
9 of 23
give inspiration
inspirationon
on
approximate 15° to minorgroove
grooveofofDNA.
DNA.The
Thementioned
mentioned structural
structural features
features give
approximate
15°
to minor groove
of DNA.
The mentioned structural features give inspiration on
further
research
of
optimizing
this
kind
of
molecules.
further research of optimizing this kind of molecules.
further research of optimizing this kind of molecules.
Figure
12.
(A)
Chemical
structure
of daunomycin;
(B)
one
strand
a DNA
duplex
complex
Figure
12.12.
(A)(A)
Chemical
structure
of of
daunomycin;
(B)(B)
oneone
strand
of aofof
DNA
duplex
complex
with
Figure
Chemical
structure
daunomycin;
strand
a DNA
duplex
complex
with
daunomycin
(PDB
code:
1D10);
(C)
chemical
structure
of
adriamycin;
and
(D)
one
strand
of
daunomycin
(PDB
code:
1D10);
(C)
chemical
structure
of
adriamycin;
and
(D)
one
strand
of
a
DNA
with daunomycin (PDB code: 1D10); (C) chemical structure of adriamycin; and (D) one strand of
a
DNA
duplex
complex
with
adriamycin
(PDB
code:
1D12).
The
orange
structure
represents
duplex
complex
with
adriamycin
code: 1D12).
orange
structure
represents
the small
molecule;
a DNA
duplex
complex
with (PDB
adriamycin
(PDBThe
code:
1D12).
The orange
structure
represents
the
small
molecule;
the purple
structureofrepresents
thethe
backbone
of
nucleic the
acid;
the molecules;
red dots
thethe
purple
structure
represents
the
backbone
nucleic
acid;
red
dots
represent
water
small molecule; the purple structure represents the backbone of nucleic acid; the red dots
represent the water molecules; the blue and red atoms in the molecule represent nitrogen and
therepresent
blue andthe
redwater
atomsmolecules;
in the molecule
represent
nitrogen
oxygen
atoms,
respectively.
The and
green
the blue
and red
atoms and
in the
molecule
represent
nitrogen
oxygen atoms, respectively. The green square represents the water molecule that interacts with the
square
represents
the water molecule
that
interacts
with the
molecule.
oxygen
atoms, respectively.
The green
square
represents
thesmall
water
molecule that interacts with the
small molecule.
small molecule.
Figure
13.
(A) Chemical
structure ofdimer
dimer ofditercalinium;
ditercalinium; and
and (B)
(B) complex
complex of
a DNA
duplex
with
Figure
13.13.
(A)
DNAduplex
duplex
with
Figure
(A)Chemical
Chemicalstructure
structureof
of dimer of
of ditercalinium; and
(B) complex
ofofaaDNA
with
ditercalinium
(PDB
code:
1D32).
The
orange
structure
represents
the
small
molecule;
the
purple
ditercalinium
structure represents
representsthe
thesmall
smallmolecule;
molecule;the
thepurple
purple
ditercalinium(PDB
(PDBcode:
code: 1D32).
1D32). The
The orange
orange structure
structure
represents
the
backboneofofnucleic
nucleicacid;
acid;the
theblue
blue and
and red
red atoms
atoms in
the
molecule
represent
structure
represents
the
backbone
in
the
molecule
represent
structure represents the backbone of nucleic acid; the blue and red atoms in the molecule represent
nitrogen
and oxygen
atoms, respectively.
nitrogen
and
nitrogen
andoxygen
oxygenatoms,
atoms,respectively.
respectively.
Actually, the specificity of DNA intercalators is the reason for drug toxicity. Molecules can bind
Actually,
thespecificity
specificityofofDNA
DNAintercalators
intercalators is the
the reason
drug
Molecules can
bind
the
reason for
for
drugtoxicity.
toxicity.
can
bind
to Actually,
unexpected
DNA sequence
for new treatment.isCryptolepine
(Figure
14A) is aMolecules
good example
for
to
unexpected
DNA
sequence
for
new
treatment.
Cryptolepine
(Figure
14A)
is
a
good
example
for
to unexpected
DNA
sequence
for
new
treatment.
Cryptolepine
(Figure
14A)
is
a
good
example
for
occasional drug discovery. Cryptolepine is isolated from Cryptolepis triangular and used as antioccasional
drug
discovery.
Cryptolepine
is isolated
from
Cryptolepis
triangular
and as
used
as antioccasional
drug
discovery.
Cryptolepine
is
isolated
from
Cryptolepis
triangular
and
used
anti-malarial
malarial and cytotoxic agent [59]. This compound can insert with C–G rich sequences [60]. The crystal
malarial
and cytotoxic
agent
[59].compound
This compoundinsert
can insert
C–G
richsequences
sequences[60].
[60]. The
crystal
and
cytotoxic
agent [59].
This
withwith
C–G
rich
The
crystal
complex
structure
indicates
that the drug can
interacts with
the
duplex
in a base stacking
insertion
complex structure indicates that the drug interacts with the duplex in a base stacking insertion
Int. J. Mol. Sci. 2016, 17, 779
10 of 24
complex structure indicates that the drug interacts with the duplex in a base stacking insertion pattern
J. Mol.
Sci. 2016, 17, 779
10 of 23
(Figure 14B).Int.
The
molecule
and two consecutive C–G base pairs form a sandwich conformation
with
two C–G rich sequences. And the hexatomic ring stacks in the middle of cytosine and guanine.
pattern (Figure 14B). The molecule and two consecutive C–G base pairs form a sandwich
Structurally, conformation
cryptolepine
mildly
twisted And
at about
6.8˝ between
rings. Besides, the
withwas
two C–G
rich sequences.
the hexatomic
ring stackstwo
in thearomatic
middle of cytosine
and guanine.
Structurally,the
cryptolepine
wasof
mildly
at about
6.8°the
between
two aromatic
rings.
charged nitrogen
can improve
stability
the twisted
complex
with
interaction
between
molecule
Besides, the charged nitrogen can improve the stability of the complex with the interaction between
and DNA duplex.
The insertion into base pair steps and the molecular dissymmetry were important
molecule and DNA duplex. The insertion into base pair steps and the molecular dissymmetry were
elements for important
this interaction.
elements for this interaction.
Figure 14. (A) Chemical structure of dimer of cryptolepine; and (B) one strand of a DNA duplex
Figure 14. (A)
Chemical
structure
of code:
dimer
of cryptolepine;
and
(B) one
of a DNA duplex
complex
with cryptolepine
(PDB
1K9G).
The orange structure
represents
thestrand
small molecule;
thecryptolepine
purple structure (PDB
represents
the backbone
nucleic
acid; thestructure
blue and red
atoms in the the
molecule
complex with
code:
1K9G).ofThe
orange
represents
small molecule;
represent nitrogen and oxygen atoms, respectively.
the purple structure represents the backbone of nucleic acid; the blue and red atoms in the molecule
represent2.1.5.
nitrogen
and oxygen
atoms,
respectively.
Small Molecules
Targeting
with
DNA Duplex through Multiple Binding Patterns
Small molecules can not only bind to DNA duplex in a single mode, but also interact with DNA
duplex in multiple
bindingwith
patterns,
which
will make
the complex
more stable
[61,62].Patterns
PBD-BIMZ
2.1.5. Small Molecules
Targeting
DNA
Duplex
through
Multiple
Binding
(Figure 15A) binds to a DNA duplex in a covalent link to a guanine base. The complex shows that the
Small molecules
can orients
not only
DNA
duplex
in aAlthough
single the
mode,
butbinding
also interact
hybrid molecule
in thebind
minorto
groove
(Figure
15B) [63].
covalent
distorts with DNA
the
DNA
helix,
the
overall
duplex
still
maintains
the
standard
B-form
conformation.
It
is
revealed
duplex in multiple binding patterns, which will make the complex more stable [61,62]. PBD-BIMZ
that covalent binding site in local region possesses specific twisted helix. By comparison, the
(Figure 15A)piperazine
binds toring
a DNA
in a covalent
to a guanine
base.
complex
shows aduplex
high flexibility
with variouslink
conformations.
Later, the
sameThe
group
reported shows that
the hybrid molecule
orients
the
(Figure
15B) [63].
Although
thebinds
covalent
binding
another ligand
(Figurein
15C)
in minor
complex groove
with the same
DNA duplex.
This hybrid
compound
to
a
guanine
in
a
covalent
link
and
the
naphthalimide
substructure
embeds
to
(A–T)
2 steps, as shown in
distorts the DNA helix, the overall duplex still maintains the standard B-form conformation. It is
Figure 15D [64]. The covalent binding will remarkably make the DNA and ligand stable. Moreover,
revealed thatbecause
covalent
local
region
helix.
manybinding
molecules site
havein
low
specificity
for possesses
sequence, thespecific
multiple twisted
patterns can
makeBy
the comparison,
the piperazine
ring
shows
a
high
flexibility
with
various
conformations.
Later,
the
same group
molecules sequence targetable.
reported another ligand (Figure 15C) in complex with the same DNA duplex. This hybrid compound
binds to a guanine in a covalent link and the naphthalimide substructure embeds to (A–T)2 steps, as
shown in Figure 15D [64]. The covalent binding will remarkably make the DNA and ligand stable.
Moreover, because many molecules have low specificity for sequence, the multiple patterns can make
the molecules sequence targetable.
Figure 15. Cont.
Figure 15. Cont.
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
11 of 24
11 of 23
Figure 15. (A) Chemical structure of PBD-BIMZ; (B) complex of a DNA duplex with PBD-BIMZ (PDB
code: 2KTT); (C) chemical structure of PBD-naphthalimide; and (D) complex of a DNA duplex with
PBD-naphthalimide (PDB code: 2KY7). The orange structure represents the small molecule; the purple
structure represents the backbone of nucleic acid; the blue and red atoms in the molecule represent
Figure 15. (A) Chemical structure of PBD-BIMZ; (B) complex of a DNA duplex with PBD-BIMZ (PDB
nitrogen and
oxygen atoms, respectively.
code: 2KTT); (C) chemical structure of PBD-naphthalimide; and (D) complex of a DNA duplex with
PBD-naphthalimide (PDB code: 2KY7). The orange structure represents the small molecule; the
purpleTargeting
structure represents
the backbone of nucleic acid; the blue and red atoms in the molecule
2.2. Small Molecules
DNA Triplex
represent nitrogen and oxygen atoms, respectively.
Single strand DNA can bind to a DNA duplex structure to form a triplex conformation DNA [65].
2.2. Small Molecules Targeting DNA Triplex
The interactions between strands are Hoogsteen or reverse Hoogsteen base pairs. Small molecules can
Single strand
DNA
can bind to
a DNA
duplex
structure
to form
a triplex
conformation
DNA
[65].
bind to triplex DNA
groove,
blocking
the
access
of other
DNA
natural
substrate
[66].
The
DNA triplex
The interactions between strands are Hoogsteen or reverse Hoogsteen base pairs. Small molecules can
can display bind
twotoforms,
intermolecular triplexes and intramolecular triplexes [67]. Intermolecular triplex
triplex DNA groove, blocking the access of other DNA natural substrate [66]. The DNA triplex
is generatedcanfrom
a DNA
chainintermolecular
of an extratriplexes
DNA structure.
Generally,
the[67].
intermolecular
display
two forms,
and intramolecular
triplexes
Intermolecular triplex has
triplex is due
generated
from
a DNA treatment
chain of an extra
DNA structure.
intermolecular
attracted attention
to the
possible
for various
cancersGenerally,
or otherthediseases.
In fact, most of
triplex has attracted attention due to the possible treatment for various cancers or other diseases. In
the DNA duplex intercalators can insert to the triplex as well [68].
fact, most of the DNA duplex intercalators can insert to the triplex as well [68].
As mentioned
above,above,
neomycin
is is
a atypical
majorDNA
DNA
groove
binder.
triplex system,
As mentioned
neomycin
typical major
groove
binder.
In triplexInsystem,
neomycin
canthe
make
the mixed
base mixed
DNAtriplexes
triplexes and
triplex
stable. stable.
The computational
neomycin can
make
base
DNA
andT–A–T
T–A–T
triplex
The computational
docking conformation
the triplex
and
neomycin isisshown
in Figure
16. The16.
computational
and
docking conformation
[69] of [69]
theoftriplex
and
neomycin
shown
in Figure
The computational
and
biophysical researches both indicate that this Watson–Hoogsteen complementarity leads to
biophysical the
researches
both
indicate
that
this
Watson–Hoogsteen
complementarity
leads
to
the
selectivity.
selectivity.
Figure 16. Computer generated model of neomycin bound to a DNA triplex. Ring I of neomycin
Figure 16. locates
Computer
generated
model
of and
neomycin
to abridging
DNAthe
triplex.
Ring
I of neomycin
in the middle
of the DNA
groove,
Ring II andbound
IV facilitate
pyrimidine
strands;
themiddle
orange, green
andDNA
purplegroove,
structuresand
represent
three IV
chains
of the DNA;
the bluethe
andpyrimidine
red atoms
locates in the
of the
Ringthe
II and
facilitate
bridging
strands;
in
the
molecule
represent
nitrogen
and
oxygen
atoms,
respectively.
the orange, green and purple structures represent the three chains of the DNA; the blue and red atoms
in the molecule represent nitrogen and oxygen atoms, respectively.
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
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12 of 23
Similar
binders,
neomycin
conjugates
are also
found
to bind
DNA
Similar to
tomajor
majorgroove
groove
binders,
neomycin
conjugates
are also
found
to with
bindthe
with
thetriplex
DNA
structures.
Computational
modeling
of
pyrene–neomycin
indicates
pyrene
will
insert
into
the
triplex structures. Computational modeling of pyrene–neomycin indicates pyrene will insert intobase
the
pairs
whenwhen
neomycin
bind with
groove
[70]. [70].
base pairs
neomycin
bind Watson–Hoogsteen
with Watson–Hoogsteen
groove
2.3.
Small Molecules
Molecules Targeting
2.3. Small
Targeting DNA
DNA Quadruplex
Quadruplex
Telomere
as aa significant
significant potential
potential strategy
strategy for
for cancer
cancer therapy.
therapy.
Telomere regulation
regulation has
has been
been regarded
regarded as
Guanosine
Guanosine rich
rich nucleic
nucleic acids
acids are
are regarded
regarded as
as aa new
new class
class of
of non-antisense
non-antisense nucleic
nucleic acids
acids with
with active
active
G-quartet
conformation
[71].
Except
for
telomerase,
G-quadruplex-forming
sequences
have
G-quartet conformation [71]. Except for telomerase, G-quadruplex-forming sequences have also
also been
been
found
in
the
promoter
regions
of
many
other
genes.
Small
molecules
can
stabilize
G-quartet
structure,
found in the promoter regions of many other genes. Small molecules can stabilize G-quartet structure,
causing
causing the
the telomerase
telomerase low
low activity
activity [72–74].
[72–74]. Therefore,
Therefore, the
the G-quadruplex
G-quadruplex structures
structures have
have attracted
attracted
more
attention
for
drug
design.
more attention for drug design.
Because
consist of
Because G-quartet
G-quartet conformations
conformations consist
of planar
planar stacked
stacked guanine
guanine bases,
bases, numbers
numbers of
of small
small
molecules
with
electron
deficient
aromatic
rings
are
identified
to
bind
[75].
As
mentioned
above,
molecules with electron deficient aromatic rings are identified to bind [75]. As mentioned above,
distamycin
typical
intercalators
for DNA
duplex.
In quadruplex
systems,
these
distamycin AAand
anddaunomycin
daunomycinareare
typical
intercalators
for DNA
duplex.
In quadruplex
systems,
compounds
are able
bind
DNA
quadruplex
structures.
The first
of G-quadruplex
and
these compounds
aretoable
to to
bind
to DNA
quadruplex
structures.
The complex
first complex
of G-quadruplex
daunomycin
was
determined
and
reported
by
Neidle
[76].
Figure
17
shows
the
four
parallel
strands
and daunomycin was determined and reported by Neidle [76]. Figure 17 shows the four parallel
and
three
daunomycin
molecules
at the end
the
complex.
This complex
that the structure
strands
and
three daunomycin
molecules
atof
the
end
of the complex.
This indicates
complex indicates
that the
shows
high
stability
with
the
molecules
stacking
on
the
end.
structure shows high stability with the molecules stacking on the end.
17. Crystal
Crystal complex of aa DNA
DNA quadruplex
quadruplex with
with daunomycin
daunomycin (PDB
(PDB code:
code: 1O0K). The orange
Figure 17.
structure represents the small molecule; the purple structure represents the backbone of nucleic acid;
in the
the molecule
molecule represent
represent nitrogen
nitrogen and
and oxygen
oxygenatoms,
atoms,respectively.
respectively.
the blue and red atoms in
It is known that distamycin A binds with the minor groove of DNA duplex. The structure of
It is known that distamycin A binds with the minor groove of DNA duplex. The structure of
G-quadruplex and distamycin A was determined and reported by Randazzo [77]. The structure
G-quadruplex and distamycin A was determined and reported by Randazzo [77]. The structure
indicates that molecule performs the similar binding to DNA duplex minor groove binding. The
indicates that molecule performs the similar binding to DNA duplex minor groove binding.
dimer of the molecule binds at the converse position of the quadruplex conformation (Figure 18). The
The dimer of the molecule binds at the converse position of the quadruplex conformation (Figure 18).
quadruplex conformation is made up of four identical parallel sequences TGGGGT. At the top of the
The quadruplex conformation is made up of four identical parallel sequences TGGGGT. At the top of
structure, three stacking daunomycins with sodium ions are located. The quadruplex conformation
the structure, three stacking daunomycins with sodium ions are located. The quadruplex conformation
resembles the inherent counterpart. The structures of daunomycins interact to the DNA grooves by
resembles the inherent counterpart. The structures of daunomycins interact to the DNA grooves
forming hydrogen bonds and van der Waals forces. The complex shows the structure is more stable
by forming hydrogen bonds and van der Waals forces. The complex shows the structure is more
when the molecules stack at the top than intercalate, because of the large termination of the molecule
stable when the molecules stack at the top than intercalate, because of the large termination of the
surface.
molecule surface.
Int. J. Mol. Sci. 2016, 17, 779
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Int. J. Mol. Sci. 2016, 17, 779
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Figure 18. Complex of a DNA quadruplex with distamycin A (PDB code: 2JT7). The orange structure
Figure
Complex
of
quadruplex
with distamycin
A (PDB
code:
2JT7).
The
orange
structure
Figure 18.
18.
Complex
of aa DNA
DNA
quadruplex
distamycin
(PDB
code:of
2JT7).
The
orange
structure
represents
the small
molecule;
the purplewith
structure
representsAthe
backbone
nucleic
acid;
the blue
represents
the
small
molecule;
the
purple
structure
represents
the
backbone
of
nucleic
acid;
the blue
and the
red atoms
the molecule
nitrogen and
oxygen atoms,
represents
smallinmolecule;
therepresent
purple structure
represents
the respectively.
backbone of nucleic acid; the blue
and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
and red atoms in the molecule represent nitrogen and oxygen atoms, respectively.
Compared to DNA duplex binding molecules, some novel kinds of molecules have been found.
These
molecules
can bind specifically
to DNA quadruplex structures, as shown in Figure 19. The
Compared
Compared to
to DNA
DNA duplex
duplex binding
binding molecules,
molecules, some novel kinds of molecules have been found.
structural and biochemical studies displayed detailed information of the interaction between small
These
can
bind
specifically
to DNA
quadruplex
structures,
as shown
Figurein
19.Figure
The structural
Thesemolecules
molecules
can
bind
specifically
DNA
quadruplex
structures,
as in
shown
molecules and
DNA
quadruplex.
Into
addition,
it also provideda
novel platform
for further
drug 19. The
and
biochemical
studies
displayed
detailed
information
of
the
interaction
between
small
molecules
structural
and
biochemical
studies
displayed
detailed
information
of
the
interaction
between
small
design targeting DNA quadruplex. The progress in this field has been reported [78].
and
DNA quadruplex.
In addition, itInalso
provideda
novel
platform novel
for further
drug for
design
targeting
molecules
and DNA quadruplex.
addition,
it also
provideda
platform
further
drug
DNA
The quadruplex.
progress in this
has been
reported
[78].
designquadruplex.
targeting DNA
Thefield
progress
in this
field has
been reported [78].
Figure 19. Typical structures of small molecules for DNA quadruplex.
3. Small Molecules Targeting RNA
3.1. Small Molecules Targeting Ribosome
The ribosomal
(rRNA)structures
is the mostof
comprehensively
among
various kinds of RNA
FigureRNA
19. Typical
small moleculesstudied
for DNA
quadruplex.
Figure 19.
structures
of small target
molecules
forits
DNA
quadruplex.
types. The ribosome
is Typical
an attractive
anti-bacterial
due to
important
function in protein
expression [79–83]. The ribosomes in prokaryotic cells mainly contain 30S and 50S subunits. The
3. Small Molecules Targeting RNA
3. Small Molecules Targeting RNA
3.1. Small
Small Molecules
Molecules Targeting
TargetingRibosome
Ribosome
3.1.
The ribosomal
ribosomal RNA
RNA (rRNA)
(rRNA) is
is the
the most
most comprehensively
comprehensively studied
studied among
among various
various kinds
kinds of
of RNA
RNA
The
types. The
due to
to its
its important
important function
function in
in protein
protein
types.
The ribosome
ribosome is
is an
an attractive
attractive anti-bacterial
anti-bacterial target
target due
expression
[79–83].
The
ribosomes
in
prokaryotic
cells
mainly
contain
30S
and
50S
subunits.
The
expression [79–83]. The ribosomes in prokaryotic cells mainly contain 30S and 50S subunits. The subunit
J. Mol.
Sci.
2016,17,
17,779
779
Int.Int.
J. Mol.
Sci.
2016,
14 of
1423
of 24
subunit 30S is for ensuring that the tRNA can locate in the correct position. The subunit 50S is
30S
is for ensuring
that theconnection.
tRNA can Various
locate inkinds
the correct
position.have
The subunit
50S is responsible
responsible
for peptide
of compounds
been identified
to bind thefor
peptide
connection.
kinds
of compounds
have been identified
to bind the subunits
of rRNA,
subunits
of rRNA,Various
including
pleuromutilin,
oxazolidinones
and aminoglycosides,
as shown
in
Figure 20pleuromutilin,
[84,85].
including
oxazolidinones and aminoglycosides, as shown in Figure 20 [84,85].
Figure 20. Typical structures of small molecules for 30S or 50S subunit of rRNA.
Figure 20. Typical structures of small molecules for 30S or 50S subunit of rRNA.
Amikacin (Figure 21A), a member of aminoglycoside antibiotics, is used to inhibit replication
(Figure
a member
of aminoglycoside
is used
to inhibit
replication
of Amikacin
various kinds
of 21A),
bacteria.
Amikacin
binds with the antibiotics,
30S subunits
of rRNA,
leading
to the of
various
kinds
of
bacteria.
Amikacin
binds
with
the
30S
subunits
of
rRNA,
leading
to
the
wrong
reading
wrong reading of message RNA and making the bacteria cell incapable of translation and growing.
of The
message
RNA and
making
the bacteria
cell the
incapable
translation
and growing.
The structure of
structure
of RNA
duplex
is nearly
same of
with
the previous
RNA-aminoglycoside
RNA
duplex
is
nearly
the
same
with
the
previous
RNA-aminoglycoside
complexes
[86–90].
One of
complexes [86–90]. One of the aromatic rings inserts into A site helix by stacking. Another
aromatic
thering
aromatic
rings
inserts
into
A
site
helix
by
stacking.
Another
aromatic
ring
forms
four
hydrogen
forms four hydrogen bonds to the H-bond acceptors nearby. These common interactions make
bonds
to the H-bond
nearby.
These
common
interactions
make
the amikacin
bind toand
RNA
the amikacin
bind toacceptors
RNA duplex
tightly,
as shown
in Figure
21B [91],
and help
maintain A1493
A1492tightly,
in the bulge
structure,
corresponding
with
themaintain
“on” state
in 30Sand
subunit.
duplex
as shown
in Figure
21B [91], and
help
A1493
A1492 in the bulge structure,
corresponding with the “on” state in 30S subunit.
Figure 21. (A) Chemical structure of amikacin; and (B) complex of a RNA duplex with amikacin
(PDB 21.
code:
4P20).
The orange
structure
representsand
the small
molecule;ofthe
purpleduplex
structure
represents
Figure
(A)
Chemical
structure
of amikacin;
(B) complex
a RNA
with
amikacin
the backbone of nucleic acid; the blue and red atoms in the molecule represent nitrogen and oxygen
(PDB code: 4P20). The orange structure represents the small molecule; the purple structure represents
atoms, respectively.
the backbone of nucleic acid; the blue and red atoms in the molecule represent nitrogen and oxygen
atoms, respectively.
Int. J. Mol. Sci. 2016, 17, 779
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Other aminoglycoside compounds have also been determined and reported. The paromomycin
(Figure 22A) is also called monomycin and aminosidine. The detailed complex of two paromomycin
molecules and an RNA fragment was solved. The molecule is located in the deep position of the RNA
groove forming hydrogen bonds with water, as shown in Figure 22B [88]. Neomycin B (Figure 22C)
is an aminoglycoside antibiotic different with paromomycin. Neomycin B contains an ammonium
group not hydroxyl group in the structure. The complex structure (Figure 22D) of neomycin B and
RNA duplex shows a similar interaction, compared to other aminoglycosides [86].
Figure 22. (A) Chemical structure of paromomycin; (B) complex of a RNA duplex with paromomycin
(PDB code: 1J7T); (C) chemical structure of neomycin B; and (D) complex of a RNA duplex with
neomycin B (PDB code: 2ET4). The orange structure represents the small molecule; the purple structure
2 nitrogen and
represents the backbone of nucleic acid; the blue and red atoms in the molecule represent
oxygen atoms, respectively.
3.2. Small Molecules Targeting Riboswitches
In molecular biology, a riboswitch is a regulatory segment of a messenger RNA (mRNA) molecule,
resulting in a change in production of the proteins encoded by the mRNA. Riboswitch consists of
an aptamer domain and an expression platform. In recent years, various kinds of riboswitches
have been reported [92–95]. Because riboswitch can bind a ligand naturally, it is an ideal target for
anti-bacterial agent.
The tetrahydrofolate (THF) riboswitch can regulate the transportation and metabolism of folate
through combining THF molecules. This riboswitch was identified to bind various kinds of folates,
such as dihydrofolate (DHF) and tetrahydrobiopterin (BH4 ). Tetrahydrobiopterin (Figure 23A), for
example, is an important cofactor of the hydroxylase enzymes of aromatic amino acid. The complex
of BH4 and THF riboswitch (Figure 23B) indicates that the placement of the pterin ring in BH4 is
identical to that of THF. Pemetrexed (Figure 23C) is a structural analog with folic acid and is also
used as chemotherapeutic drug in treatment. The crystal complex of riboswitch and pemetrexed
indicates that the compound binds to the RNA structure almost identically as THF, as shown in
Figure 23D [96]. Both structures reveal that reduced folates are primarily recognized by the RNA
through their pterin moiety.
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Int. J. Mol. Sci. 2016, 17, 779
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Figure 23. (A) Chemical structure of tetrahydrobiopterin; (B) complex of a RNA duplex with
Figure 23.
(A) Chemical(PDB
structure
of tetrahydrobiopterin;
complex
RNA duplex
with
tetrahydrobiopterin
code: 4LVX);
(C) chemical structure of(B)
pemetrexe;
andof(D)a complex
of a
tetrahydrobiopterin
(PDB
code: 4LVX);
(C)4LVY).
chemical
structure
ofrepresents
pemetrexe;
andmolecule;
(D) complex of
RNA duplex with
pemetrexed
(PDB code:
The orange
structure
the small
the purple
represents
thecode:
backbone
of nucleic
acid; thestructure
blue and red
atoms in the
a RNA duplex
withstructure
pemetrexed
(PDB
4LVY).
The orange
represents
themolecule
small molecule;
represent
nitrogen
and oxygen
respectively.
the purple
structure
represents
theatoms,
backbone
of nucleic acid; the blue and red atoms in the molecule
represent nitrogen and oxygen atoms, respectively.
Recently, some aminoglycosides are identified to bind with the riboswitch RNA, including
ribostamycin and paromomycin [97].To understand the biochemical elements for the significant
riboswitch
specificity,
the complexesare
of paromomycin
(Figure
and
ribostamycin
(Figure
24C)including
Recently,
some
aminoglycosides
identified to
bind24A)
with
the
riboswitch
RNA,
with
neomycin
riboswitch
RNA
were
resolved.
The
complexes
of
the
two
structures
indicate
that
ribostamycin and paromomycin [97].To understand the biochemical elements for thethe
significant
two helix structures of the rRNA formed a consecutive A-form helical structure through stacking
riboswitch
specificity,
the
complexes
of
paromomycin
(Figure
24A)
and
ribostamycin
(Figure
24C)
between two G–C base pairs, as shown in Figure 24B,D. In the two complex structures, the 6′
with neomycin
riboswitch
RNA
were
resolved.
The
complexes
of
the
two
structures
indicate
that
substructures of the two molecules locate at a close area, near the hinge region between the upper
and the
lower helix
the two helix
structures
ofstem.
the rRNA formed a consecutive A-form helical structure through stacking
between two G–C base pairs, as shown in Figure 24B,D. In the two complex structures, the 61 substructures
of the two molecules locate at a close area, near the hinge region between the upper and the lower
helix stem.
Figure 24. Cont.
Figure 24. Cont.
Int. J. Mol. Sci. 2016, 17, 779
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Int. J. Mol. Sci. 2016, 17, 779
17 of 23
Figure 24. (A) Chemical structure of paromomycin; (B) complex of a neomycin riboswitch RNA
with paromomycin (PDB code: 2MXS); (C) chemical structure of ribostamycin; and (D) complex of
Figure 24. (A) Chemical structure of paromomycin; (B) complex of a neomycin riboswitch RNA with
a neomycin riboswitch RNA with ribostamycin (PDB code: 2N0J). The orange structure represents the
paromomycin (PDB code: 2MXS); (C) chemical structure of ribostamycin; and (D) complex of a
small molecule; the purple structure represents the backbone of nucleic acid; the blue and red atoms in
neomycin riboswitch RNA with ribostamycin (PDB code: 2N0J). The orange structure represents the
the molecule
represent
and oxygen
atoms,
small molecule;
the nitrogen
purple structure
represents
the respectively.
backbone of nucleic acid; the blue and red atoms
in the molecule represent nitrogen and oxygen atoms, respectively.
3.3. Small Molecules Targeting MicroRNA
3.3. Small Molecules Targeting MicroRNA
MicroRNAs (miRNA), a class of noncoding RNA molecules, contain ~22 length nucleotides,
MicroRNAs
(miRNA),
a class
of noncoding
RNA
molecules, contain
~22 length
nucleotides,
which function
for gene
expression
[98–100].
In order
to understand
the structure
of miRNA
and the
which function for gene expression [98–100]. In order to understand the structure of miRNA and the
interaction between miRNA and small molecules, computational high throughput screenings play
interaction between miRNA and small molecules, computational high throughput screenings play
an important
role, because computers could drastically speed up the identification and optimization
an important role, because computers could drastically speed up the identification and optimization
of compounds
targeting
miRNA,
compared
drugdiscovery
discovery
strategy.
of compounds
targeting
miRNA,
comparedtototraditional
traditional drug
strategy.
Recently,
Shi
et
al.
discovered
that
AC1MMYR2
(Figure
25)
was
an
efficient
and selective
inhibitor
Recently, Shi et al. discovered that AC1MMYR2 (Figure 25) was an efficient
and selective
of microRNA-21
through
in
silicon
virtual
screening
[101].
The
pre-miRNA-21
was
modeled
inhibitor of microRNA-21 through in silicon virtual screening [101]. The pre-miRNA-21 was modeled by
by MC-Fold/MC-Sym
pipeline.
Forty-eightpredicted
predicted compounds
compounds were
selected
by AutoDock.
MC-Fold/MC-Sym
[102] [102]
pipeline.
Forty-eight
were
selected
by AutoDock.
Finally,
AC1MMYR2
identified
inhibittumor
tumorproliferation
proliferation and
Finally,
AC1MMYR2
waswas
identified
to to
inhibit
andmigration.
migration.
Figure
25.25.Chemical
ofAC1MMYR2.
AC1MMYR2.
Figure
Chemical structure
structure of
3.4. Small
Molecules
Targeting
Long
Non-CodingRNA
RNA
3.4. Small
Molecules
Targeting
Long
Non-Coding
noncoding
(lncRNA)
has shown
been shown
play important
functional
roles in
LongLong
noncoding
RNA RNA
(lncRNA)
has been
to play to
important
functional
roles in development
development
and
disease
processes
[103–106].
Influenza
A
virus
contains
eight
separated,
singleand disease processes [103–106]. Influenza A virus contains eight separated, single-stranded
RNAs
stranded RNAs that encode 13 kinds of proteins. The RNA dependent RNA polymerase (RdRp) can
that encode 13 kinds of proteins. The RNA dependent RNA polymerase (RdRp) can recognize
recognize a specific RNA conformation, lncRNA in particular, regulating the beginning of replication
a specific RNA conformation, lncRNA in particular, regulating the beginning of replication and
and transcription process [107,108]. A small molecule (DPQ, Figure 26A) was found to bind with the
transcription
process
A small
molecule
(DPQ, Figure
26A)
was found
to the
bind
with the
lncRNA [109].
The [107,108].
crystal structure
showed
small molecule
locates in
the major
groove of
(A–A)–
lncRNA
[109].
The
crystal
structure
showed
small
molecule
locates
in
the
major
groove
of
the
(A–A)–U
U loop (Figure 26B). The bindings of small molecule widen the major groove close the position of
loop G14–C21
(Figure 26B).
The bindings
of small molecule widen the major groove close the position of
and G13–C22
base pairs.
G14–C21 and G13–C22 base pairs.
Int. J. Mol. Sci. 2016, 17, 779
Int. J. Mol. Sci. 2016, 17, 779
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18 of 23
Figure 26. (A) Chemical structure of DPQ; and (B) structure of a RNA promoter complex with DPQ
Figure 26. (A) Chemical structure of DPQ; and (B) structure of a RNA promoter complex with DPQ
(PDB code: 2LWK). The orange structure represents the small molecule; the purple structure
(PDB code: 2LWK). The orange structure represents the small molecule; the purple structure represents
represents the backbone of nucleic acid; the blue and red atoms in the molecule represent nitrogen
the backbone
of nucleic acid; the blue and red atoms in the molecule represent nitrogen and oxygen
and oxygen atoms, respectively.
atoms, respectively.
4. Conclusions
4. Conclusions
Nucleic acid drug discovery is a sophisticated system and comprises of a large number of stages,
including
target
selection,
binding
verification, system
potent inhibitor
screening,
compound
Nucleic acid
drug
discovery
is asite
sophisticated
and comprises
of and
a large
number of
optimization.
Small
molecule
targeting
nucleic
acid
is
still
a
tremendous
challenge.
Due
to the
low
stages, including target selection, binding site verification, potent inhibitor screening, and
compound
specificity of DNA or RNA binders, high rate of the failure in clinical trials is the obstacle of nucleic
optimization. Small molecule targeting nucleic acid is still a tremendous challenge. Due to the low
acid drug discovery. The progress of nucleic acid drug discovery needs the development of structural
specificity of DNA or RNA binders, high rate of the failure in clinical trials is the obstacle of nucleic
biology and other related technologies.
acid drugDNAs
discovery.
The
progress oftarget
nucleic
drugsmall
discovery
needsfor
theinstance
development
of structural
as the
fundamental
of acid
various
molecules,
antibiotics
and
biology
and
other
related
technologies.
antitumor agents, have been verified. It is obvious that small molecules bind with different
DNAs
as theto
fundamental
target
of various Small
small molecules
molecules,can
forbind
instance
antibiotics
and
antitumor
mechanisms
different DNA
conformation.
to DNA
duplex in
various
kinds
of mechanisms,
including
covalent binding,
insertion,
and some
Formechanisms
triplex and to
agents,
have
been verified.
It is obvious
that small
molecules
bindmultifunction.
with different
quadruplex,
however, the intercalation
or insertion
is the
binding
mode forkinds
small of
molecules.
different
DNA conformation.
Small molecules
can bind
to common
DNA duplex
in various
mechanisms,
In particular,
majority
of such and
smallsome
molecules
contain planar
aromatic
systems. Such
including
covalentthe
binding,
insertion,
multifunction.
For triplex
andring
quadruplex,
however,
substructure
can
keep
the
complex
more
stable.
the intercalation or insertion is the common binding mode for small molecules. In particular, the
RNA attracts less attention than DNA targets. Nevertheless, recently, much progress has been
majority of such small molecules contain planar aromatic ring systems. Such substructure can keep
made in discovering small molecule inhibitor stargeting to RNA with high specificity and bioactivity.
the complex more stable.
In silico virtual screening for novel inhibitors targeting RNA has produced original small molecule
RNA
attracts less attention than DNA targets. Nevertheless, recently, much progress has been
RNA binders.
made in discovering
stargeting
tocan
RNA
with ahigh
specificity
bioactivity.
In summary,small
small molecule
molecules inhibitor
targeting nucleic
acids
regulate
large
number ofand
biological
In silico
virtual However,
screeningmajor
for novel
inhibitors
targeting
RNA
produced
original
processes.
challenges
and issues
are yet
to behas
resolved.
Therefore,
thesmall
studymolecule
and
of promising small molecules targeting nucleic acids strategies is ongoing.
RNAdevelopment
binders.
In summary, small molecules targeting nucleic acids can regulate a large number of biological
Acknowledgments: We thank the other academic staff members in Aiping Lu and Ge Zhang’s group at Hong
processes. However, major challenges and issues are yet to be resolved. Therefore, the study and
Kong Baptist University. We also thank Hong Kong Baptist University for providing critical comments and
development
of promising
small
targeting
acidsResearch
strategies
is (HKBU
ongoing.
technical support.
This study
wasmolecules
supported by
the Hongnucleic
Kong General
Fund
478312) and
HKBU Faculty Research Grant (FRG2/14-15/010).
Acknowledgments: We thank the other academic staff members in Aiping Lu and Ge Zhang’s group at Hong Kong
Author
Contributions:
Wang Kong
wrote Baptist
the manuscript;
Yuanyuan
Yu and critical
Chao Liang
contributed
the
Baptist
University.
We also Maolin
thank Hong
University
for providing
comments
and technical
manuscript
for literature
research;
Lu and
Ge General
Zhang revised
and Fund
approved
the manuscript.
support.
This study
was supported
byAiping
the Hong
Kong
Research
(HKBU
478312) and HKBU Faculty
Research Grant (FRG2/14-15/010).
Conflicts of Interest: The authors declare no conflict of interest.
Author Contributions: Maolin Wang wrote the manuscript; Yuanyuan Yu and Chao Liang contributed the
manuscript
for literature research; Aiping Lu and Ge Zhang revised and approved the manuscript.
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