Cyclic Peptide Design

332 Pages·2019·13.363 MB·English

by  Gilles Goetz

Methods in
Molecular Biology 2001
Gilles Goetz Editor
Cyclic Peptide
Design
M M B
ETHODS IN OLECULAR IO LO GY
SeriesEditor
JohnM.Walker
School of Lifeand MedicalSciences
University ofHertfordshire
Hatfield, Hertfordshire,AL109AB,UK
Forfurther volumes:
http://www.springer.com/series/7651
Cyclic Peptide Design
Edited by
Gilles Goetz
Hit Discovery and Optimization, Pfizer R&D, Groton, CT, USA
Editor
GillesGoetz
HitDiscoveryandOptimization
PfizerR&D
Groton,CT,USA
ISSN1064-3745 ISSN1940-6029 (electronic)
MethodsinMolecularBiology
ISBN978-1-4939-9503-5 ISBN978-1-4939-9504-2 (eBook)
https://doi.org/10.1007/978-1-4939-9504-2
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Preface
If you are used to the Methods in Molecular Biology series, you will notice right away that
thereareveryfewmethodsandvirtuallynomolecularbiologyinthisparticularedition.This
bookwillcertainlystandoutinyourcollection.Veryfewchaptersofthisbookarewrittenin
thetypicalMiMBformat,butthisdoesnottakeanythingawayfromthevalueoftheworks
presentedhere!
Interests in cyclic peptide design, synthesis, and applications keep growing since this
class of chemicals has become a credible alternative source of new drug leads on par with
traditional small molecules. Cyclic peptides are particularly suited to bridge the chemical
spacegapbetweensaidsmallmoleculesandproteinsandantibodies.
This book covers strategies to improve cell permeability, intestinal permeability, and
metabolicstability,whicharethetypicalliabilitiesassociatedwithcyclicpeptides,toenhance
protein-protein recognition, and to build upon nature’s cyclic peptides and macrocycles.
Chapters also cover key peptide screening and display strategies, as well as important
syntheticapproachestowardscyclicandhelicalpeptides.
Researchers within the pharmaceutical industry as well as scientists and studentsin the
bioorganic, medicinal, and natural product chemistry fields will find this book a critical
resourceandago-toreference.
Groton,CT,USA GillesGoetz
v
Contents
Preface ..................................................................... v
Contributors................................................................. ix
1 DesignPrinciplesforIntestinalPermeabilityofCyclicPeptides............... 1
AlanM.Mathiowetz
2 StrategiestoEnhanceMetabolicStabilities................................. 17
BhaveshKhatri,VenkateswaraRaoNuthakki,
andJayantaChatterjee
3 DesigningCell-PermeableMacrocyclicPeptides ............................ 41
GeorgeAppiahKubi,PatrickG.Dougherty,andDehuaPei
4 ComputationalMethodsforStudyingConformationalBehaviors
ofCyclicPeptides....................................................... 61
FanJiangandHaoGeng
5 ComputationalOpportunitiesandChallengesinFindingCyclic
PeptideModulatorsofProtein–ProteinInteractions......................... 73
FergalDuffy,NikunjMaheshwari,Nicolae-ViorelBuchete,
andDenisShields
6 DesignofCyclicPeptidesasProteinRecognitionMotifs..................... 97
YeChe
7 DesignandSyntheticStrategiesforHelicalPeptides......................... 107
LichengTu,DongyuanWang,andZigangLi
8 ClickChemistryforCyclicPeptideDrugDesign............................ 133
AdelAhmedRashad
9 FrontierBetweenCyclicPeptidesandMacrocycles.......................... 147
PhilippErmert,AnatolLuther,PeterZbinden,
andDanielObrecht
10 BuildinguponNature’sFramework:OverviewofKeyStrategies
TowardIncreasingDrug-LikePropertiesofNaturalProduct
CyclopeptidesandMacrocycles........................................... 203
Maria-JesusBlanco
11 DesignofOxytocinAnalogs ............................................. 235
KazimierzWi´sniewski
12 DNA-EncodedMacrocyclicPeptideLibrary ............................... 273
ZhengrongZhu,AlexShaginian,LaShadricC.Grady,
ChristopherP.Davie,KennethLind,SandeepPal,
PraewThansandote,andGrahamL.Simpson
13 PeptideDisplayTechnologies ............................................ 285
AnthonyPittandZekeNims
vii
viii Contents
14 DiscoveryofFunctionalMacrocyclicPeptidesbyMeans
oftheRaPIDSystem.................................................... 299
ChristosTsiamantas,ManuelE.Otero-Ramirez,
andHiroakiSuga
15 GeneticSelectionswithSICLOPPSLibraries:Toward
theIdentificationofNovelProtein–ProteinInteractionInhibitors
andChemicalTools..................................................... 317
FranciscoCastilloandAliTavassoli
Index ...................................................................... 329
Contributors
GEORGEAPPIAHKUBI (cid:1) DepartmentofChemistryandBiochemistry,TheOhioState
University,Columbus,OH,USA
MARIA-JESUS BLANCO (cid:1) SageTherapeutics,Inc.,Cambridge,MA,USA
NICOLAE-VIOREL BUCHETE (cid:1) SchoolofPhysics,UniversityCollegeDublin,Dublin,Ireland
FRANCISCOCASTILLO (cid:1) SchoolofChemistry,UniversityofSouthampton,Southampton,UK
JAYANTACHATTERJEE (cid:1) MolecularBiophysicsUnit,IndianInstituteofScience,Bangalore,
India
YECHE (cid:1) DiscoverySciences,PfizerInc.,Groton,CT,USA
CHRISTOPHERP.DAVIE (cid:1) GlaxoSmithKline,Cambridge,MA,USA
PATRICKG.DOUGHERTY (cid:1) DepartmentofChemistryandBiochemistry,TheOhioState
University,Columbus,OH,USA
FERGALDUFFY (cid:1) SchoolofMedicineandMedicalScience,UniversityCollegeDublin,Dublin,
Ireland;UCDConwayInstituteofBiomolecularandBiomedicalResearch,University
CollegeDublin,Dublin,Ireland
PHILIPPERMERT (cid:1) PolyphorLtd.,Allschwil,Switzerland
HAOGENG (cid:1) LaboratoryofComputationalChemistryandDrugDesign,StateKey
LaboratoryofChemicalOncogenomics,PekingUniversityShenzhenGraduateSchool,
Shenzhen,China
LASHADRICC.GRADY (cid:1) GlaxoSmithKline,Cambridge,MA,USA
FANJIANG (cid:1) LaboratoryofComputationalChemistryandDrugDesign,StateKey
LaboratoryofChemicalOncogenomics,PekingUniversityShenzhenGraduateSchool,
Shenzhen,China
BHAVESH KHATRI (cid:1) MolecularBiophysicsUnit,IndianInstituteofScience,Bangalore,India
ZIGANGLI (cid:1) StateKeyLaboratoryofChemicalOncogenomics,PekingUniversity,Shenzhen
GraduateSchool,Peking,China
KENNETHLIND (cid:1) GlaxoSmithKline,Cambridge,MA,USA
ANATOLLUTHER (cid:1) PolyphorLtd.,Allschwil,Switzerland
NIKUNJMAHESHWARI (cid:1) SchoolofMedicineandMedicalScience,UniversityCollegeDublin,
Dublin,Ireland;UCDConwayInstituteofBiomolecularandBiomedicalResearch,
UniversityCollegeDublin,Dublin,Ireland
ALANM.MATHIOWETZ (cid:1) PfizerWorldwideResearchandDevelopment,Cambridge,MA,
USA
ZEKENIMS (cid:1) OrbitDiscoveryLtd.,Oxford,UK
VENKATESWARARAONUTHAKKI (cid:1) MolecularBiophysicsUnit,IndianInstituteofScience,
Bangalore,India
DANIELOBRECHT (cid:1) PolyphorLtd.,Allschwil,Switzerland
MANUELE.OTERO-RAMIREZ (cid:1) DepartmentofChemistry,GraduateSchoolofScience,The
UniversityofTokyo,Bunkyo,Tokyo,Japan
SANDEEPPAL (cid:1) GlaxoSmithKline,Stevenage,UK
DEHUA PEI (cid:1) DepartmentofChemistryandBiochemistry,TheOhioStateUniversity,
Columbus,OH,USA
ANTHONYPITT (cid:1) OrbitDiscoveryLtd.,Oxford,UK
ADELAHMEDRASHAD (cid:1) CollegeofMedicine,DrexelUniversity,Philadelphia,PA,USA
ix
x Contributors
ALEXSHAGINIAN (cid:1) GlaxoSmithKline,Cambridge,MA,USA
DENISSHIELDS (cid:1) SchoolofMedicineandMedicalScience,UniversityCollegeDublin,Dublin,
Ireland;UCDConwayInstituteofBiomolecularandBiomedicalResearch,University
CollegeDublin,Dublin,Ireland
GRAHAM L.SIMPSON (cid:1) GlaxoSmithKline,Stevenage,UK
HIROAKISUGA (cid:1) DepartmentofChemistry,GraduateSchoolofScience,TheUniversityof
Tokyo,Bunkyo,Tokyo,Japan
ALITAVASSOLI (cid:1) SchoolofChemistry,UniversityofSouthampton,Southampton,UK
PRAEWTHANSANDOTE (cid:1) GlaxoSmithKline,Stevenage,UK
CHRISTOSTSIAMANTAS (cid:1) DepartmentofChemistry,GraduateSchoolofScience,The
UniversityofTokyo,Bunkyo,Tokyo,Japan
LICHENGTU (cid:1) StateKeyLaboratoryofChemicalOncogenomics,PekingUniversity,Shenzhen
GraduateSchool,Peking,China
DONGYUANWANG (cid:1) StateKeyLaboratoryofChemicalOncogenomics,PekingUniversity,
ShenzhenGraduateSchool,Peking,China
KAZIMIERZWIS´NIEWSKI (cid:1) FerringResearchInstituteInc.,SanDiego,CA,USA
PETERZBINDEN (cid:1) PolyphorLtd.,Allschwil,Switzerland
ZHENGRONG ZHU (cid:1) GlaxoSmithKline,Cambridge,MA,USA
Chapter 1
Design Principles for Intestinal Permeability of Cyclic
Peptides
Alan M. Mathiowetz
Abstract
Oneofthemostexcitingfacetsofcyclicpeptidesisthattheyhavethepotentialtobeorallybioavailable,
despitehavingphysicalpropertieswellbeyondthetraditional“Rule-of-5”chemistryspace(Lipinskietal.,
AdvDrugDelivRev.23(1):3–25,1997).Animportantcomponentofmeetingthischallengeistodesign
cyclic peptides with good intestinal permeability. Here we discuss the design principles for intestinal
permeabilitythathavebeendevelopedinrecentyear.Theseprinciplescanbesubdividedintothreeregimes:
physicalpropertyguidelines,designstrategiesforthemacrocyclicring,anddesignstrategiesforsidechains.
Themostimportantoverallaimsaretominimizesolvent-exposedpolaritywhilekeepingsize,flexibility,and
lipophilicitywithinfavorableranges,therebyallowingpeptidechemiststoachieveintestinalpermeabilityin
additiontootherimportantpropertiesfortheircompounds,suchassolubilityandbindingaffinity.Herewe
describeavarietyofdesignstrategiesthathavebeendevelopedtohelppeptidechemistsinthisendeavor.
Keywords Cyclicpeptides,Oralbioavailability,Intestinalpermeability,Physicalproperties,Intramo-
lecularhydrogenbonding,N-methylation,BeyondRule-of-5
1 Introduction
Cyclic peptides are an exciting therapeutic modality, with the
potential to inhabit an attractive “middle space” between tradi-
tionalsmallmoleculesandbiologicals[1].Anintriguingpossibility,
as exemplified by cyclosporine A [2], is that cyclic peptides can be
discoveredwhichhavesignificantoralbioavailability,providingthe
convenience and compliance of oral dosing while retaining the
ability to bind to larger sites such as protein-protein interfaces.
Cyclic peptides often lie just beyond the “Rule-of-5” [3], which
describes a physical property space with an improved likelihood of
oral bioavailability, but recent work has identified a wide range of
cyclicpeptideswithsignificantoralbioavailability[4–11],including
thoseshowninTable1.
A recent analysis of the properties of orally bioavailable drugs
[12] described the physical properties most important for oral
GillesGoetz(ed.),CyclicPeptideDesign,MethodsinMolecularBiology,vol.2001,https://doi.org/10.1007/978-1-4939-9504-2_1,
©SpringerScience+BusinessMedia,LLC,partofSpringerNature2019
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