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! ! ! ! ! ! ! ! ! Oligosaccharides!in! Drug!Discovery! ! 2014! ! ! ! ! Development of Oligosaccharides in drug discovery ! ! ! Introduction! ! 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.!! ! ! Saccharides:!multifunctional!biological!molecules! ! 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! www.glycomar.com! synthesise! in# vitro! making! current! drug! discovery! and! development! activity! largely! dependent! on! nature!for!the!generation!of!screening!libraries.! ! ! Oligosaccharide!therapeutics:! ! 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! www.glycomar.com! 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]) )) ) ) ) ) -