Download Oligosaccharides in drug discovery

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Oligosaccharides!in!
Drug!Discovery!
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2014!
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! Development of Oligosaccharides in drug discovery
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Introduction!
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Glycobiology! is! the! branch! of! biology! concerned! with! the! study! of! structure,! biosynthesis,! and!
function! of! saccharides! (sugar! chains),! which! may! exist! purely! or! conjugated! to! other! biological!
molecules! to! form! glycoconjugates.! The! study! of! such! molecules! is! technically! challenging! as! no!
sequencing! tool,! such! as! that! used! in! proteomics! or! genomics,! is! available.! However,! following! on!
from! genomics! and! proteomics,! there! is! increasing! recognition! of! the! importance! of! carbohydrateI
based! molecules! in! basic! cellular! processes.! This! has! resulted! in! more! extensive! glycomic! studies! in!
the! areas! of! glycosylation! of! therapeutic! proteins,! glycosylation! patterns! in! cell! recognition,! cellular!
glycoprofiling! studies! in! cancer! and! other! diseases,! correlation! between! activity! and! sulphation!
patterns! in! glycosaminoglycans,! and! the! improved! chemical! analysis! and! synthesis! of! carbohydrate!
molecules.!
!
Glycobiology!offers!enormous!untapped!potential!in!the!discovery!of!new!therapeutics!derived!from!
saccharides!or!other!molecules!which!target!the!biosynthesis!and!function!of!saccharides.!!
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Saccharides:!multifunctional!biological!molecules!
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Saccharides! offer! potential! chemical! diversity! orders! of! magnitude! greater! than! their! protein! and!
nucleic!acid!counterparts[1].!For!example,!DNA!can!give!256!4Iunit!structures;!amino!acids!can!give!
16000!4Iunit!structures,!whereas!the!nine!common!monosaccharides!have!the!theoretical!ability!to!
generate! nearly! 16! million! 4Iunit! structures[2].! The! level! of! chemical! information! encoded! in!
saccharides!is!therefore!unrivalled.!
!
!
Graph!taken!from:!!Turnbull!&!Field!!2007!Nature!Chemical!Biology!3(2),!pp74I77!
!
Saccharides! have! multiple! functions! which! makes! them! relevant! to! almost! any! area! of! biological!
research.!They!are!ubiquitously!present!on!cell!surfaces,!mediating!the!interaction!of!cells!with!other!
cells,!with!the!extracellular!matrix!and!with!effector!molecules.!The!glycosylation!of!protein!molecules!
is!also!critical!for!their!function,!bioavailability!and!halfIlife.!Polysaccharides!and!glycoconjugates!also!
play! a! major! structural! role! in! all! connective! tissues.! Oligosaccharides,! which! are! short! chains!
(nominally! 2I10! monosaccharides)! of! sugars! derived! from! larger! polysaccharides! or! synthesised! in!
their! own! right,! are! widely! studied! to! identify! functional! groups! within! complex! glycoconjugates! or!
polysaccharides.! The! expression! of! saccharides,! which! in# vivo# occurs! by! the! ruleIdriven! action! of! a!
multiple! synthetic! enzymes,! is! much! more! complex! than! that! of! proteins! or! nucleotides! which! are!
template! driven! processes.! ! All! but! the! very! smallest! saccharides! have! proven! very! difficult! to!
© GlycoMar!Limited!
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synthesise! in# vitro! making! current! drug! discovery! and! development! activity! largely! dependent! on!
nature!for!the!generation!of!screening!libraries.!
!
!
Oligosaccharide!therapeutics:!
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The!central!role!of!saccharides!in!cellular!interactions!means!that!novel!oligosaccharides!are!of!value!
in!R&D!programmes!addressing!a!wide!range!of!therapeutic!areas![3,!4],!including:!
!
• Inflammation!
• Immunity!
• Oncology!
• Neurodegenerative!disease!
• Infection!
!
Regulation!of!the!immune!system!is!a!key!area!of!interest!to!glycobiologists,!due!to!the!central!roles!
of! carbohydrateIbased! molecules! such! as! glycoproteins! and! glycosaminoglycans! in! cellIcell!
recognition,!cell!signalling!and!infection.!With!increasing!understanding!of!the!inflammation!process!
in! a! range! of! disorders! including! vascular! disease! (atherosclerosis,! thrombosis,! diabetes),!
neurodegeneration! (Alzheimer’s,! Multiple! sclerosis),! cancer! and! orthopaedic! illnesses! (arthritis,!
Ankylosing! spondylitis),! there! is! wide! scope! for! the! further! application! of! novel! carbohydrateIbased!
drugs.!!
!
Oligosaccharides-in-use-as-drugs-or-in-development:!
The!use!of!carbohydrateIbased!drugs!is!in!its!infancy,!although!several!are!well!known!(see!Table!1).!
In! addition! to! ‘monosaccharideIinspired’! drugs! such! as! influenza! treatment! Tamiflu! (oseltamivir,!
Roche),! two! blockbuster! drugs,! Acarbose! (Bayer)! and! heparin,! stand! out.! Both! saccharides! were!
isolated,!and!reached!the!clinic,!before!a!detailed!structureIactivity!relationship!had!been!carried!out.!
Heparin!is!the!key!example!of!a!major!carbohydrateIbased!molecule,!which!has!been!developed!for!
medical!use!in!antiIcoagulant!therapies.!Low!molecular!weight!heparins!(eg.!Certoparin,!Dalteparin)!
and!various!derivatives!(Fondaparinux!–!fully!synthetic)!have!been!developed!to!improve!efficacy!and!
halfIlive,!and!some!are!now!being!trialled!for!nonIthrombotic/vascular!applications!(eg.!Certoparin!for!
inflammatory! aspects! of! Alzheimer’s! disease).! It! is! only! comparatively! recently! that! the! antiI
inflammatory!properties!of!heparin!have!been!the!subject!of!drug!discovery!research!&!development.!
!
Delivery-and-immunogenicity:The!drugs!listed!in!Table!1!have!overcome!some!of!the!perceived!limitations!of!sugarIbased!molecules!
in!terms!of!synthesis,!delivery!and!immunogenicity.!Although!many!still!require!intravenous!delivery,!
several! are! available! orally! (e.g.! Pentosan! polysulphate)! and! further! research! is! targeting! the!
improvement! of! oral! availability! by! reducing! compounds! to! their! smallest! active! components,! or! by!
combining!with!other!molecules!(e.g.!sulodexide).!Improvements!in!synthesis!have!meant!that!some!
compounds!can!be!synthesised!(e.g.!Fondaparinux),!and!small!active!components!can!be!selected!or!
modified!to!improve!efficacy.!No!major!problems!have!been!reported!with!immunogenicity!either!in!
animal!trials!or!as!approved!drugs,!using!synthetic!or!animal!derived!material,!including!that!obtained!
from!marine!invertebrates.!!Approval!of!marine!derived!heparinoids!is!more!common!in!China!than!in!
Western!Countries!and!there!are!a!number!of!phase!I!and!phase!II!trials!ongoing!in!the!East.!
© GlycoMar!Limited!
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Table&1.&Examples&of&carbohydrate6based&drugs&in&use&or&in&development&
Company)
Compound)
Activity)/)disorder)
Development)
Numerous)
Heparin)and)derivatives:)in)particular)low)
molecular)weight)forms)
Arixtra)(fondraparinux))–)synthetic)heparin)
pentasaccharide)
Generic)now)available)(Dr)Reddy’s))
Auranofin)(Ridaura):)organogold)monosaccharide)
Zanamivir)(Relenza):)modified)monosaccharide)
Topiramate)(Topamax):)modified)monosaccharide)
Acarbose)(Glucobay))(PseudoAoligosaccharide))
AntiAcoagulants)
Since)1940’s)
Factor)Xa)inhibitor,)DVT))&)pulmonary)embolism)
1982)
AntiArheumatic))
AntiAinfluenza)(neuraminidase)inhibitor))
AntiAepileptic)
Type)II)diabetes)
AlphaAglucosidase,)alphaAamylase)inhibitor.)
Cystitis)(interest)in)development)for)CJD))
1983)
1992)
1987)
1990)
Various)cardiovascular)indications)
Marketed)since)
1980’s)
Phase)IIa)
Phase)III)
GSK)
Astellas)
GSK)
Johnson)&)Johnson)
Bayer)
OrthoAMcNeil)Janssen)
Pharmaceutical)
Alfa)Wassermann)
Merion)Pharmaceuticals)
Sanofi)Aventis)
Cantex)Pharmaceuticals)
(previously)ParinGenix))
Hunter)Fleming)(now)
Newron))
Progen)(Australia))
)
Elmiron)(Pentosan)polysulphate))
Sulodexide)(Vessel™):)mixture)of)LMW)heparin)and)
dermatan)sulphate)
MERA102:)uLMW)heparin)
Idrabiotaparinux,)biotinylated)synthetic)heparin)
pentasaccharide)
PGX100:)OAdesulphated)heparin)
HF0420)–)low)molecular)weight)oligosaccharide)
PIA88)(Phosphomannopentaose)sulphate))
PG545:)fully)synthetic)heparan)sulphate)mimetic)
Endotis)Pharma)
)
EP80061)–)synthetic)oligsaccharide)
EP80031)–)synthetic)oligosaccharide)
EP37151)–)oral)fondaparinux)
EP217609)–)biotinylated)thrombin)inhibitor)
coupled)to)pentasaccharide)
Biotec)Pharmacon)
BetaAglucan)
Oral)uLMW)heparin)for)DVT)
Biotinylated)idraparinux)for)the)treatment)DVT)and)
pulmonary)embolism)
OAdesulphated)heparin)for)cardiac)ischemiaAreperfusion)
injury,)COPD.)Used)in)AML.)
Prevention)of)antiAcancer)induced)neuropathy)
(neuroprotective))
Heparan)sulphate)mimetic)–)AntiAangiogenic/antiA
metastatic.)Adjuvant)therapy)for)postAresection)
hepatocellular)carcinoma)
Heparan)sulphate)mimetic)–)AntiAangiogenic/antiA
metastatic.)
AntiAmetastatic,)heparanase)inhibitor)
Hematopoietic)stem)cell)mobilization)
Anticoagulant)
Indirect)factor)Xa)and)direct)thrombin)(Factor)IIa))inhibitor)
that)can)be)neutralized)quickly)and)effectively)without)
rebound)effect)by)a)specific)antidote:)avidin)
Wounds,)Cancer,)IBS,)Asthma))
© GlycoMar)Limited)
www.glycomar.com)
1996)
Phase)I/)Phase)II)
Discontinued))
Phase)III)
Late)PreAclinical))
Discontinued))
Discontinued)
Discontinued)
Discontinued)
Preclinical)
Marinova)
GlycoMar)/)Verona)Pharma)
AlgiPharma)
Wu)et)al)[5])
China)Ocean)University*)
Sun)et)al[6])
Fucoidan)
GLY145)–)glycosaminoglycan)
Oligo)G)from)alginate)
Heparinoid)911)A)Sulphated)
polymannuroguluronate)(from)alginate))
Polymannuronic)acid)propyl)sulphate)(PMS))
Heparinoid)916)(from)chitosan))
Propylene)glycol)alginate)sodium)sulphate)(PSS))
Propylene)glycol)mannate)sulphate)(PGMS)"
HS971)–)Oligo)mannuronate)from)alginate)
Immunity,)Osteoarthritis,)HSVA1,)AntiAoxidant))
AntiAinflammatory)
Cystic)Fibrosis))
HIV/AIDS)
Phase)I)&)II)
Preclinical)
Phase)I)
Phase)IIa)
Cerebral)Ischemia.)Influenza))
Atherosclerosis)
AntiAangiocardiopathy))
Posterior)capsular)opacification)
Alzheimer’s))
Phase)IIa)
Phase)III)
Available)in)China)
Available)in)China)
Phase)IIb)
HS203:)oligosaccharide)complex)of)chromium)(III))
and)oligomannuronic)acid)
AntiADiabetes)
Preclinical))
)
*Patent)relating)to)use)of)PMS)in)influenza)appears)to)be)owned)by)the)University.)
© GlycoMar)Limited)
www.glycomar.com)
Oligosaccharide-libraries-for-drug-discovery-research:Native)glycoconjugates)and)polysaccharides)have)limited)value)in)drug)discovery)research)due)to)their)
large)size)(MW)10)–)1000)kDa))and)structural)heterogeneity,)although)heparin)is)a)notable)historical)
exception)which)has)been)used)in)its)native)form)(manufactured)form)bovine)lung)or)porcine)gastric)
mucosa).) Oligosaccharides) generated) from) native) molecules) offer) the) opportunity) to) identify) active)
functional) subunits) and) of) revealing) cryptic) activity.) Heparin) provides) an) example) of) a) blockbuster)
saccharide) that) has) progressed) from) unfractionated) polysaccharide,) to) low) molecular) weight)
polysaccharide,)and)now)synthetic)pentasaccharide,)through)the)application)of)glycomic)tools.)
)
Oligosaccharide)libraries)clearly)have)value)for)drug)discovery)research)in)a)wide)range)of)diseases)[7].)
Such) libraries) are) becoming) increasingly) available) from) a) small) number) of) specialist) suppliers) (see)
Appendix) 1)) largely) based) on) glycosaminoglycans) such) as) heparin) and) chondroitin) sulphate,) marine)
polysaccharides) such) as) alginate) and) chitosan,) and) oligosaccharides) derived) from) common) plant)
polysaccharides.) All) natural) oligosaccharides) are) subject) to) varying) degrees) of) structural) and) size)
heterogeneity,) which) pose) problems) in) detailed) structure) activity) studies.) The) wider) availability) of)
oligosaccharide) synthesisers) (e.g.) Glyconeer)) will) have) a) significant) impact) on) the) availability) of)
oligosaccharides)for)drug)discovery)research,)by)reducing)reliance)on)natural)products)and)improving)
the)quality)(homogeneity)/)purity))of)oligosaccharides.)
)
The) unique) structures) and) sulphation) patterns) of) marine) derived) sugars) are) being) increasingly)
recognised) and) investigated) [8].) Several) polysaccharides) and) oligosaccharides) are) in) use) as)
nutraceuticals,)with)pharmaceutical)development)of)others)in)preclinical)and)clinical)trials,)and)a)few)
drugs) on) the) market) in) China.) Depolymerised) and) low) molecular) weight) forms) dominate) clinical)
investigations)with)oral)delivery)possible)and)no)reported)problems)with)immunogenicity.)Marinova)
(Australia))are)involved)in)the)development)of)fucoidanTbased)products)from)seaweeds)[9],)using)inT
house)modulation)of)sulphation)and)acetylation.)They)are)investigating)applications)in)cardiovascular,)
infection,)oncology)and)inflammation)areas,)as)are)several)other)research)and)commercial)labs.)This)
parallels)the)activity)by)IFREMER,)France.)Other)compounds)have)been)brought)forward)by)academic)
research)groups,)in)particular)a)Brazilian)team)from)Rio)de)Janeiro,)often)in)association)with)industrial)
partners)eg.)SanofiTAventis)(sea)squirt)heparin).)A)significant)number)of)oligosaccharide)drugs)derived)
from)seaweeds)have)been)developed)by)China)Ocean)University,)including)marketed)drugs.)
)
)
Table-2.-Examples-of-marine<derived-carbohydrate<based-therapeutic-moleculesCompound)
Source)
Activity)
Status)
Chondroitin)sulphates)
Galactofucan)sulphate)(GFS))
Mussels)
Seaweed)
Marinova,)Australia)
Fucosylated)chondroitan)
sulphate)
Sea)cucumber)
Invertebrate)Heparin)
Oligo)G!
Heparinoid)911)T)Sulphated)
polymannuroguluronate))
Polymannuronic)acid)propyl)
sulphate)(PMS))
Heparinoid)916)
Propylene)glycol)alginate)sodium)
sulphate)(PSS))
Propylene)glycol)mannate)
sulphate)(PGMS))
HS203)
Nutraceutical)
Nutraceutical)/)Clinical)
Sea)squirt)
Alginate)
Alginate)(seaweed))
Joint)repair)/)maintenance)
Attenutates)herpes)virus)
infections.)Improved)mobilization)
of)hematopoetic)stem)cells)
PTselectin)mediated)antiT
inflammatory)effects)/)unique)
antiTcoagulant)properties)
Arterial)thrombosis)
Cystic)Fibrosis))
HIV/AIDS)
Alginate)(seaweed))
Cerebral)Ischemia)
Phase)IIa)
Chitosan)
(crustacean)shell))
Alginate)(seaweed))
Atherosclerosis)
Phase)III)
AntiTangiocardiopathy))
Available)in)China)
Alginate)(seaweed))
Posterior)capsular)opacification)
Available)in)China)
Laminaria'japonica)
Diabetes)
Preclinical))
© GlycoMar)Limited)
www.glycomar.com)
Preclinical)
Preclinical)
Phase)I)
Phase)IIa)
(seaweed))
Seaweed)
Heparinoid)971)
Alzheimer’s)Disease)
Phase)IIb)
)
Glycan-Arrays:Due)to)the)high)level)of)interest)and)applications)of)glycobiology)in)human)and)animal)medicine)there)
has)been)a)concerted)effort)to)develop)glycan)arrays)and)glycochips)for)use)in)biological)and)medical)
applications.)Due)to)the)complexity)of)the)carbohydrates)involved)there)has)been)a)perceivable)delay)
in)the)development)of)suitable)arrays,)however)more)recent)development)of)oligosaccharide)libraries)
have) made) arrays) promising) tools) for) screening) potential) activity) in) novel) compounds) and) are)
becoming)an)important)tool)in)drug)discovery.))
)
Glycan)arrays)provide)a)high)throughput)screening)method)used)to)study)interaction)of)a)large)
numbers)of)saccharide)structures)with)target)molecules,)and)can)be)used)to)identify)carbohydrate)
interactions)which)may)be)of)value)in)drug)discovery.))The)arrays)are)often)superior)to)screening)
techniques)such)as)enzymeT)linked)immunosorbent)assays)(ELISA))as)thousands)of)interactions)can)be)
analysed)at)one)time,)and)only)minute)amounts)of)analyte)and)ligand)are)required)for)reliable)results.)
Oligosaccharides)which)have)either)been)isolated)or)synthesised)are)covalently)attached)to)glass,)
plastic)or)gold)services)or,)are)placed)on)beads)in)fibreT)optic)wells)[7].)More)recent)screening)
methods)also)use)oligosaccharides)which)have)been)paired)with)a)linker)on)the)reducing)terminus)and)
then)covalently)attached)to)the)slide)–)fluorescent)labelling)is)used)to)highlight)interactions)as)well)as)
mass)spectrometry)analysis,)and)DNA)printing)and)scanning)equipment)can)be)used)to)evaluate)the)
array.)
)
One)particularly)valuable)example)of)where)glycan)arrays)have)been)employed)is)during)the)discovery)
of)HIV)vaccine)candidates)where)epitope)mapping)of)HIVT)related)antibodies)was)performed.)The)
information)obtained)was)vital)in)identifying)carbohydrate)based)vaccinations)[7].))
Oligosaccharide-based-drug-discovery:GlycoMar) is) a) biopharmaceutical) company) uniquely) focused) on) the) development) of) novel) antiT
inflammatory) therapies) based) on) saccharide) molecules) from) a) diverse) selection) of) predominantly)
marine) organisms.) This) combination) of) diverse) biological) source) with) a) targeted) but) inherently)
diverse)chemistry)has)generated)a)hit)rate)100T1000)times)higher)than)conventional)small)molecule)
screening.))
)
)
)
)
)
© GlycoMar)Limited)
www.glycomar.com)
References)
1.)
Turnbull,)J.E.)and)R.A.)Field,)Emerging'glycomics'technologies.)Nat)Chem)Biol,)2007.)3(2):)p.)
74.)
2.)
Maeder,)T.,)Sweet'medicines'8'Sugars'play'critical'roles'in'many'cellular'functions'and'in'
disease.'Study'of'those'activities'lags'behind'research'into'genes'and'proteins'but'is'
beginning'to'heat'up.'The'discoveries'promise'to'yield'a'new'generation'of'drug'therapies.)
Scientific)American,)2002.)287(1):)p.)40T47.)
3.)
Koeller,)K.M.,)Emerging'themes'in'medicinal'glycoscience.)Nature)Biotechnology,)2000.)18(8):)
p.)835T841.)
4.)
Dube,)D.H.)and)C.R.)Bertozzi,)Glycans'in'cancer'and'inflammation'8'potential'for'therapeutics'
5.)
6.)
7.)
8.)
9.)
and'diagnostics.)Nature'Reviews'Drug'Discovery,)2005.)4:)p.)477T488.)
Wu,)Y.L.,)et)al.,)Sulfated'polymannuroguluronate'inhibits'Tat8induced'SLK'cell'adhesion'via'a'
novel'binding'site,'a'KKR'spatial'triad.)Acta)Pharmacol)Sin,)2011.)32(5):)p.)647T54.)
Sun,)S.,)et)al.,)Microanalysis'of'oligosaccharide'HS203'in'beagle'dog'plasma'by'postcolumn'
fluorescence'derivatization'method.)Carbohydr)Polym,)2012.)89(2):)p.)661T6.)
Seeberger,)P.H.,)Synthesis'and'medical'applications'of'oligosaccharides.)Nature,)2007.)446:)p.)
1046T1051.)
Laurienzo,)P.,)Marine'polysaccharides'in'pharmaceutical'applications:'an'overview.)Mar)
Drugs,)2010.)8(9):)p.)2435T65.)
Fitton,)J.H.,)Therapies'from'fucoidan;'multifunctional'marine'polymers.)Mar)Drugs,)2011.)
9(10):)p.)1731T60.)
)
Appendix-1-<-Oligosaccharide-suppliers)
Aglyco)T)http://www.aglyco.com/)
Elicityl)T)http://www.elicitylToligotech.com/)
Grampian)Enzymes)–)Aberdeen,)UK)
Iduron)T)http://www.iduron.co.uk/)
Qingdao)BZTOligo)Co)T)http://marineToligo.com/index.html
© GlycoMar)Limited)
www.glycomar.com)
GlycoMar)is)a)
biopharmaceutical)
company,)located)at)the)
European)Centre)for)
Marine)Biotechnology)in)
Scotland,)UK.)The)
company)has)created)a)
unique)combination)of)
marine)biology,)
glycobiology,)and)drug)
discovery.))
)
)
)
)
GlycoMar)Limited)
European)Centre)for)
Marine)Biotechnology)
Scottish)Marine)Institute)
Dunbeg,)Oban,)Argyll)
Scotland)PA37)1QA)
)
Tel:)+44)(0)1631)559)370)
Fax:)+44)(0)1631)559)010)
)
Email:)[email protected])
))
)
)
)
)
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