Venoms to drugs : venom as a source for the development of human therapeutics

339 Pages·2015·4.754 MB·English

by  Glen F King, C R Ganellin, Salvatore Guccione

Venoms to Drugs
Venom asa Sourceforthe Development of Human Therapeutics
RSC Drug Discovery Series
Editor-in-Chief:
Professor DavidThurston,King’sCollege, London,UK
Series Editors:
Professor DavidRotella,Montclair State University, USA
Professor Ana Martinez,Medicinal Chemistry Institute-CSIC, Madrid, Spain
Dr David Fox, Vulpine Science and Learning, UK
Advisor to the Board:
Professor Robin Ganellin, University College London,UK
Titles in the Series:
1: Metabolism,Pharmacokinetics andToxicity ofFunctional Groups
2: Emerging Drugs and Targetsfor Alzheimer’sDisease;Volume1
3: Emerging Drugs and Targetsfor Alzheimer’sDisease;Volume2
4: Accounts inDrug Discovery
5: New Frontiersin Chemical Biology
6: AnimalModelsfor Neurodegenerative Disease
7: Neurodegeneration
8: G Protein-Coupled Receptors
9: Pharmaceutical Process Development
10: Extracellular and Intracellular Signaling
11: New Synthetic Technologies inMedicinalChemistry
12: New Horizonsin Predictive Toxicology
13: Drug Design Strategies: Quantitative Approaches
14: NeglectedDiseases andDrug Discovery
15: BiomedicalImaging
16: Pharmaceutical Salts andCocrystals
17: Polyamine Drug Discovery
18: Proteinasesas Drug Targets
19: Kinase Drug Discovery
20: Drug Design Strategies: Computational Techniques andApplications
21: Designing Multi-Target Drugs
22: Nanostructured Biomaterials forOvercoming BiologicalBarriers
23: Physico-Chemical andComputationalApproaches to Drug Discovery
24: Biomarkersfor Traumatic Brain Injury
25: Drug Discovery from NaturalProducts
26: Anti-Inammatory Drug Discovery
27: New Therapeutic Strategies for Type 2 Diabetes:SmallMolecules
28: Drug Discovery for PsychiatricDisorders
29: Organic Chemistryof Drug Degradation
30: ComputationalApproaches to Nuclear Receptors
31: TraditionalChinese Medicine
32: SuccessfulStrategies for the Discovery ofAntiviral Drugs
33: Comprehensive BiomarkerDiscovery and ValidationforClinical
Application
34: Emerging Drugs and Targets forParkinson’sDisease
35: Pain Therapeutics; Currentand Future TreatmentParadigms
36: Biotherapeutics: Recent Developmentsusing Chemical and Molecular
Biology
37: Inhibitors ofMolecular Chaperones asTherapeutic Agents
38: Orphan Drugs and Rare Diseases
39: Ion ChannelDrug Discovery
40: MacrocyclesinDrugDiscovery
41: Human-basedSystems forTranslational Research
42: Venoms to Drugs: Venom asa Sourceforthe Development of Human
Therapeutics
How to obtain future titles on publication:
Astandingorderplanisavailableforthisseries.Astandingorderwillbring
deliveryof each new volume immediately onpublication.
For further information please contact:
BookSalesDepartment,RoyalSocietyofChemistry,ThomasGrahamHouse,
Science Park, Milton Road, Cambridge, CB4 0WF, UK
Telephone: [phone], Fax: [phone]
Email:[email protected]
Visit our website atwww.rsc.org/books

Venoms to Drugs
Venom as a Source for the Development
of Human Therapeutics
Edited by
Glenn F. King
Institute for MolecularBioscience,
The Universityof Queensland,Australia
Email: [email protected]
RSCDrugDiscoverySeriesNo.42
PrintISBN:978-1-84973-663-3
PDFeISBN:978-1-84973-787-6
ISSN:2041-3203
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
©TheRoyalSocietyofChemistry2015
Allrightsreserved
Apartfromfairdealingforthepurposesofresearchfornon-commercialpurposesorfor
privatestudy,criticismorreview,aspermittedundertheCopyright,DesignsandPatents
Act1988andtheCopyrightandRelatedRightsRegulations2003,thispublicationmaynot
bereproduced,storedortransmitted,inanyformorbyanymeans,withouttheprior
permissioninwritingofTheRoyalSocietyofChemistryorthecopyrightowner,orinthe
caseofreproductioninaccordancewiththetermsoflicencesissuedbytheCopyright
LicensingAgencyintheUK,orinaccordancewiththetermsofthelicencesissuedbythe
appropriateReproductionRightsOrganizationoutsidetheUK.Enquiriesconcerning
reproductionoutsidethetermsstatedhereshouldbesenttoTheRoyalSocietyofChemistry
attheaddressprintedonthispage.
TheRSCisnotresponsibleforindividualopinionsexpressedinthiswork.
Theauthorshavesoughttolocateownersofallreproducedmaterialnotintheirown
possessionandtrustthatnocopyrightshavebeeninadvertentlyinfringed.
PublishedbyTheRoyalSocietyofChemistry,
ThomasGrahamHouse,SciencePark,MiltonRoad,
CambridgeCB40WF,UK
RegisteredCharityNumber207890
Forfurtherinformationseeourwebsiteatwww.rsc.org
Preface
“You would do well to mark the various forms of the Viper.… And from the
wound she makes there oozes a discharge like oil or, it may be, bloody or
colourless, while the skin around starts up into a painful lump, oen
greenish, now crimson, or again livid of aspect.At other times it engenders
amassofuid,andaboutthewoundsmallpimpleslikeblistersriseabbily
fromtheskin,whichlooksscorched.Andallaroundspreadulcers,someat
a distance, others by the wound, emitting a dark blue poison; and over the
whole body the piercing bane eats its way with acute inammation; and in
the throat and about the uvula retchings following fast upon one another
convulse the victim. The body is oppressed with failures of sense in every
part,andforthwithinthelimbsandloinsisseatedaburdening,dangerous
weakness, andheavy darknesssettles inthe head”.
From Theriacaby Nicanderof Colophon, 2nd century BCE
(Translationfrom the Greek poemby
A.S.F. Gow and A.F. Scholeld)
Humans have been simultaneously enthralled and terried by venomous
animalsforthousandsofyears.Forsome,themerestglimpseofaspideror
snakeprovokesanirrationalanddebilitatingfear.Butformanythethreatis
all too real—venomous animals continue to have devastating effects on
human populations, with an estimated 50000 people dying each year from
snake bitein India alone.
Yet, strangely, and perhaps perversely, venomous animals have proved to
be a source of life-saving drugs. Captopril, the rst blockbuster antihyper-
tensivedrug,wasderivedfromapeptidicinhibitorofangiotensin-converting
enzyme found in the venom of a Brazilian viper. Captopril has saved many
morelivesthanthissnakeanditscloserelativeshavekilledintheirmillions
of years on the planet. There are currently six FDA-approved drugs derived
RSCDrugDiscoverySeriesNo.42
VenomstoDrugs:VenomasaSourcefortheDevelopmentofHumanTherapeutics
EditedbyGlennF.King
©TheRoyalSocietyofChemistry2015
PublishedbytheRoyalSocietyofChemistry,www.rsc.org
vii
viii Preface
from animal venoms, and they are used to treat a variety of ailments,
including hypertension, diabetes, and chronicpain.
Research into venoms as a potential source of therapeutics greatly inten-
sied over the past decade, with much activity in both academia and the
pharmaceutical industry. There are several reasons for this. The dwindling
output of new molecular entities combined with the recent success of bio-
logicsledtorenewedinterestinnaturalsources,suchasvenoms,asasource
of drug leads. Increasing patient acceptance of injectable therapies created
a more conducive environment for the development of peptide and protein
drugs. And nally, our improved understanding of the chemical and phar-
macological complexity of animal venoms facilitated the development of
morefocussedscreensto discover venommoleculeswithdesired biological
activity.Asaresultofthisincreasedresearchactivity,thecurrentpipelineof
venom-derived drugs is larger than ever, with several venom peptides
currently undergoing clinical trials and many more in various stages of
preclinicaldevelopment.
Thisbookattemptstocapturethecurrentexcitementandmostimportant
developmentsintheeldofvenoms-baseddrugdiscovery.Thebookbegins
with an overview of the extant suite of venomous animals and their toxin
repertoires before drilling down to detailed case studies and issues
surrounding optimisation and manufacturing of venom-derived peptide
drugs.
Eachvenomhasaspecicecologicalrole,andthereforeunderstandingthe
context in which a venom has evolved is important for focussing drug
discovery efforts. It makes no sense, for example, to focus on neurotoxic
spider venoms if one is seeking a drug that modulates blood pressure; hae-
motoxic snake venoms are likely to be a better bet. Thus, the book begins
with a comprehensive overview of venom evolution and how this relates to
biodiscovery. Chapter 2 provides an overview of the diverse range of
disulde-rich scaffolds found in animal venoms. These scaffolds have
provided a robust structural framework for evolving peptides that are
simultaneously potent, selective, and stable. Despite their potential for
providing high target potency and selectivity, these disulde-rich scaffolds
have an inherently high degree of chemical and pharmacological plasticity,
thereby facilitating the design of analogues with greater potential forthera-
peutic application.
Chapters3and4reviewthewiderangeofapproachesthatcanbeusedfor
venoms-baseddrugdiscovery,includingrecentdevelopmentsinproteomics,
transcriptomics, high-throughput target-based screens, and automated
electrophysiology. In addition, the case is made for the power of more
traditional bioassaysusingwhole animals or isolated tissues.
The complex venoms of reptiles, aquatic cone snails, scorpions, and
spiders have evolved independently. Each of these venoms has a specic
ecologicalpurpose,withachemicalandpharmacologicalcompositiontuned
for this role. In Chapters 5–8, experts on these venoms examine their
potential as a sourceofdrugleads.
Preface ix
Chapter 9 details the development of analgesic drugs derived from
disulde-rich peptides in the venom of cone snails. Chapter 10 provides
a detailed case study of the ongoing and highly promising development of
a sea anemone peptide for the treatment of a range of autoimmune and
inammatory diseases,includingmultiple sclerosis and psoriatic arthritis.
Most venom components being considered for drug development are
disulde-rich peptides, which creates signicant challenges for large-scale
production and drug delivery. Chapter 11 discusses chemical approaches
thatcanbeusedtomodulatethestabilityandbioavailabilityofdisulde-rich
venom peptides, while the nal chapter provides real-life examples of how
syntheticchallengeshavebeenovercomeinproductionofthevenom-derived
drugs eptibatide,ziconitide, and exenatide.
Thisprimarygoalofthisbookistoprovideacomprehensiveresourcefor
chemists and biologists who are interested in venoms as a source of new
drugs,aswellasmembersofthelaypublicwhoarefascinatedbythenotion
that venomous creatures can also have positive impacts on human health.
However,Ialsohopethatthisbookwillinspirethetoxinologyandmedicinal
chemistrycommunitiestoworktogether,withcross-fertilisationofexpertise
andknowledge,oncreatinganewgenerationofvenom-derivedtherapeutics.
Iwouldliketoconveymysinceregratitudetothecontributingauthorswho
willingly gave their time and energy towards this project. My thanks and
appreciationalsogototheteamattheRoyalSocietyofChemistry,including
Gwen Jones, Rosalind Searle, Helen Prasad, Cara Sutton, Sarah Salter, and
RowanFrame,fortheirsupportandencouragement.Finally,Iwouldliketo
thankmyfamilyandallthemembersofmylaboratoryfortheirpatienceand
forbearance during the productionof this book.
Glenn King