Download What does the transition state of this reaction look like?

What does the transition state of
this reaction look like?
• Note that a key step in the previous mechanism is the
loss of an alkoxy (sugar) moiety from the position
(C2) next to the carboxylate group.
• This creates a carbocation (Sn1 process), which is
sp2 hybridized.
• The initial substrate is sp3 hybridized at C2
• Thus it was decided to try to synthesize and test
compounds which had a double bond to C2, with the
prospect of identifying something which bound tighter
than the substrate and which could, therefore,
function as an effective inhibitor.
Chemical evolution of neuraminidase inhibitors
• Note that lower Ki values correspond to more active inhibitors
• The final product, Relenza (Zanamivir), has a positively
charged guanidinium cation (southern end of molecule)
• Thus, it is too polar to be absorbed orally and must be
administered by inhalation.
Further chemical evolution of neuraminidase inhibitors
While the C5 substituent (glycerol side chain) bound to a
polar pocket, some of the more recent analogs have
shown there is also a hydrophobic pocket, which can
bind more hydrophobic C5 side chains, such as the
tertiary amide side chain of I.
• Note that the actual reaction intermediate (lower left) involves a resonancestabilized carbocation (with oxygen providing electrons to stabilize the C2
carbocation.
• Thus it was decided that the double bond of Relenza (Zanamivir) might be in a
somewhat incorrect position for optimal binding.
• To prepare a stable compound with the double bond in the optimal position, they
had to replace the oxygen of the six-membered ring with a carbon (called a carbon
isostere).
•Note the improvement in activity as the double bond position is altered.
Further chemical evolution of neuraminidase inhibitors
• Thus a series of compounds was prepared having an
appropriately placed C=C and an adjacent hydrophobic
group (in this case a substituted ether linkage).
• The most active of these (above) has a branched side
chain (3-pentyl side chain) on the ether.
• Due to the improvement in inhibitory activity, it was
possible to remove the highly polar guanidinium side chain
and replace it with a slightly less polar amine side chain.
Evolution leading to the final product, Tamiflu.
• The carboxylic acid of GS 4071 is still too polar.
• Thus, they replaced the acid with an ester, which can be
hydrolyzed by esterases.
• Compounds related to II (above) are currently in clinical
trials. These seem to show a further improvement in
selectivity against viruses.
Other Drugs to Treat Influenza
Antiviral Drugs
• amantadine (Symmetrel): used
prophylactically against influenza A in
high-risk individuals.
• rimantidine (Flumadine): used for
treatment and prophylaxis of influenza
A.
Mechanism of Action of
Amantadine and Rimantadine
• These agents were discovered by random
screening and are now known to interfere
with a viral ion channed called matriz (M2)
protein.
• This causes an inhibition of uncoating of the
virus.
• At high concentrations, they also buffer the
pH of the endosomes and prohibit the acidic
environment needed for Hemaglutanin (HA)
to fuse the viral membrane with that of the
endosome.
What is HSV?
• HSV = Herpes Simplex Virus
• HSV-1 is the ‘usual’ cause of cold sores
• HSV-2 is the ‘usual’ cause of genital
herpes
• Both types look the same under the
microscope and share about 50% of
their DNA.
What is the difference
between HSV-1 and HSV-2?
• Both types infect the body’s mucosal surfaces,
usually mouth or genitals, and then establish latency
in the nervous system.
• For both types, at least two-thirds of the infected
people have no symptoms, or symptoms too mild to
notice.
• However, both types can recur and spread, even
after a period in which there were no symptoms.
HSV-1 and HSV-2
http://www.healthscout.com/ani
mation/68/21/main.html
Link
Link
The differences
• HSV-1 usually establishes latency in the
trigeminal ganglion, a collection of nerve
cells near the ear. Then it tends to
recur on the lower lip or face.
• HSV-2 usually establishes latency in
sacral ganglion at the base of the spine.
From there, it recurs in the genital area.
HSV-1
• However, one can have HSV-1 both genitally and
orally.
• HSV-1 is usually mild, especially when it infects the
lips, face, or genitals.
• However, HSV-1 can recur in the eye, causing ocular
herpes, which can lead to blindness, and can even
spread spontaneously to the brain, causing herpes
encephalitis, which can lead to death.
HSV-2
• 22% of adult Americans have HSV-2
• Like HSV-1, HSV-2 symptoms are usually
mild, so mild, in fact, that two-thirds of
infected people don’t know they have it.
• HSV-2 rarely causes complications or
spreads to other parts of the body.
• Oral HSV-2 infections are rare. But even
when an infection does occur, recurrent oral
outbreaks are uncommon.
Transmission of HSV-2
• In the first year of HSV-2 infection, people shed the
virus from the genital area about 6 to 10% of those
days when they are asymptomatic. This decreases
over time and can also be further lessened by the
use of oral medication. Sex should be avoided in the
presence of symptomatic lesions.
• Having a previous HSV-1 infection seems to provide
some immunity to an HSV-2 infection. This is
probably the reason that oral HSV-2 infections are
rare, given the studies which show that a significant
proportion of the population practices oral sex.
How severe an infection?
• HSV is a lifelong illness
• But HSV-2 usually produces only mild symptoms or
signs or no symptoms at all. However, HSV-2 can cause
recurrent painful genital sores in many adults, and HSV2 infection can be severe in people with suppressed
immune systems.
• Another factor is how long a person has had the
infection. It seems to decrease in severity over time,
for reasons which are unclear.
Symptoms
• If signs and symptoms occur during the
first episode, they can be quite
pronounced. The first episode usually
occurs within two weeks after the virus
is transmitted, and the sores typically
heal within two to four weeks.
• Other signs and symptoms during the
primary episode may include a second
crop of sores, or flu-like symptoms,
including fever and swollen glands.
Is there a cure?
• There is no treatment that can
cure herpes, but antiviral
medications can shorten and
prevent outbreaks during the
period of time the person takes the
medication.
Vaccines?
• NIH is now in the midst of Phase III
clinical trial of an HSV-2 vaccine. This
vaccine appears to be about 50%
effective.
• If approved, it would be available in
2008.
Antiviral Chemotherapy for HSV
• There are several prescription antiviral
medications for controlling herpes outbreaks,
include acyclovir (Zovirax), valacyclovir
(Valtrex), famcyclovir (Famvir), and
pencyclovir.
• Acyclovir was the original and prototypical
member of this class
• Valacyclovir and famcyclovir are prodrugs of
acyclovir and pencyclovir respectively, with
improved oral bioavailability.
Chemotherapy for HSV
O
O
HN
N
N
H2N
N
N
H2N
N
HN
N
H2N
HO
O
O
O
O
Acyclovir (Zovirax)
Valacyclovir (Valtrex),
O
N
HN
H2N
O
N
HN
N
N
HO
H2N
N
N
AcO
OH
OAc
pencyclovir
Famcyclovir (Famvir),
Mechanism of Action of
Antivirals to treat HSV
• Both acyclovir and pencyclovir work by
interfering with viral replication, effectively
slowing the replication rate of the virus, and
providing a greater opportunity for the
immune response to intervene.
• All drugs in this class depend on the activity
of the viral thymidine kinase to convert the
drug to a monophosphate form and
subsequently interfere with viral DNA
replication.
DNA Virus
• Recall that HSV is a DNA virus (influenza was an
RNA virus)
• In general, more drugs are available to treat DNA
viruses than for RNA viruses (excluding those used to
treat HIV).
• Most of the drugs available for treatment of DNA
viruses have been developed against herpesviruses.
• Diseases include cold sores, genital herpes,
chickenpox, shingles, mononucleosis, etc.
Acyclovir (ZOVIRAX)
• Discovered by random compound screening
and introduced into the market in 1981.
• It was the first non-toxic herpes drug to be
used systemically.
• It is used for the treatment of infections due to
both HSV-1 and HSV-2.
http://www.cat.cc.md.us/biotut
orials/dna/dnareppr.html
• http://www.dnalc.org/ddnalc/resources/s
angerseq.html
• Aciclovir interferes with DNA synthesis, but must first become activated.
•To become activated, Aciclovir must be phosphorylated (3x)
• However, Aciclovir itself is not a good substrate for mammalian kinases,
thus it relies on the viral thymidine kinase to become phosphorylated the
first time.
• This is good, since the drug cannot interfere with DNA synthesis in cells
that are not infected with the virus, thus reducing the toxicity of the drug.
• The second and third phosphorylations, however, are performed by the
cellular thymidylate kinase.
•Aciclovir triphosphate is mistaken for
deoxyguanosine triphosphate.
• However, since it lacks the 3’-OH
group, it cannot be linked to the
adjacent residue in the ‘usual’
fashion.
Valacyclovir
• Valaciclovir is an esterified version of
aciclovir, that has greater oral
bioavailability.
Penciclovir
• Penciclovir is used primarily as a cream
(it has poor oral bioavailability) to treat
herpesvirus infections.
• It is the active ingredient in the cold sore
medications Denavir and Fenistil..
Famciclovir
• Famciclovir is a di-esterified version of penciclovir
• The ester groups give the drug better oral
bioavailability
• To treat shingles, it is taken three times a day for
seven days.
• To treat genital herpes, it is taken twice a day for five
days.
Major members of the herpesvirus
group of the family Herpesviridae
• Herpes simplex viruses: HSV-1 and
HSV-2
• Cytomegalovirus (CMV)
• Varicella-zoster virus (VZV)
• Epstein-Barr virus (EBV)
Varicella-zoster virus (VZV)
• The Varicella zoster virus
(VZV) is one of the eight
herpes viruses known to
affect humans (and other
vertebrates). It commonly
causes chickenpox in
children and shingles later
in life.
Shingles
Treatment of Varicella Infection
• Acyclovir has been shown to reduce fever
and skin lesions in patients with varicella
and it use is recommended in healthy
patients over 18 years of age.
Acyclovir (ZOVIRAX)
Cytomegalovirus
• Cytomegalovirus (CMV) is a common
virus that infects most people during
their life. Most people are infected in
early childhood (under 3 years of age)
or in the teenage years. Usually there
are no symptoms of CMV infection.
• Since most CMV infections are mild and
usually do not cause long-term
problems, most people don't even know
they are infected.
• However, CMV can cause problems in a
developing baby if the mother gets the
infection during pregnancy.
Cytomegalovirus (CMV)
• After a person has a CMV infection, the
virus stays in the body but is not active.
The virus can reactivate months or
years later, which occurs most often
when a person's immune system is
weakened.
Cytomegalovirus (CMV)
• Anyone with a weakened immune system is
at risk for problems with CMV infection. A
weakened immune system can be related to
infection with the human immunodeficiency
virus (HIV) or medical treatments.
• Medical treatments that can weaken the
immune system include: chemotherapy,
radiation therapy, steroids, and stem cell or
organ transplantation.
Cytomegalovirus (CMV)
• A few people will have symptoms such as sore throat,
fever, headache and fatigue. People who have
weakened immune systems may develop severe
symptoms, such as pneumonia or infections of the
eyes, liver, or intestinal tract. People with HIV
infection should be sure to let their doctor know if
they are having any painless blurring of their vision,
"floaters" in the eye, light flashes, areas of blindness,
or shortness of breath.
Treatment of CMV Infection
• Gangiclovir, a nucleoside analog of acyclovir,
inhibits CMV replication and reduces the severity
of CMV syndromes, such as retinitis and
gastrointestinal disease.
O
N
HN
H2N
O
O
N
HN
N
N
H2N
HO
N
N
O
OH
Deoxyguanosine
H2N
N
N
HO
HO
O
N
HN
O
OH
Acyclovir
Gangciclovir
Ganciclovir
Ganciclovir is used to treat or prevent cytomegalovirus
Gangciclovir for ocular use is marketed under the trade
name Vitrasert.
Valganciclovir
Valganciclovir is a more orally bioavailable version of this
drug.
Epstein-Barr Virus (EBV)
• EBV is the etiologic agent of infectious
mononucleosis
• Symptoms include fever, tender lymph
nodes, sore throat, mental fatigue
• Treatment is usually supportive
• Acyclovir can decrease replication of
EBV in culture, but has little impact on
clinical illness.