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Advances in Experimental Medicine and Biology 1366 Shibo Jiang Lu Lu Editors Virus Entry Inhibitors Stopping the Enemy at the Gate Advances in Experimental Medicine and Biology Volume 1366 SeriesEditors WimE.Crusio,InstitutdeNeurosciencesCognitivesetIntégratives d’Aquitaine,CNRSandUniversityofBordeaux,PessacCedex,France HaidongDong,DepartmentsofUrologyandImmunology MayoClinic,Rochester,MN,USA HeinfriedH.Radeke,InstituteofPharmacology&Toxicology ClinicoftheGoetheUniversityFrankfurtMain,FrankfurtamMain,Hessen, Germany NimaRezaei,ResearchCenterforImmunodeficiencies,Children’sMedical Center,TehranUniversityofMedicalSciences,Tehran,Iran OrtrudSteinlein,InstituteofHumanGenetics LMUUniversityHospital,Munich,Germany JunjieXiao,CardiacRegenerationandAgeingLab,InstituteofCardiovas- cularScience,SchoolofLifeScience,ShanghaiUniversity,Shanghai,China Advances in Experimental Medicine and Biology provides a platform for scientific contributions in the main disciplines of the biomedicine and the life sciences. This series publishes thematic volumes on contemporary researchintheareasofmicrobiology,immunology,neurosciences,biochem- istry, biomedical engineering, genetics, physiology, and cancer research. Covering emerging topics and techniques in basic and clinical science, it bringstogethercliniciansandresearchersfromvariousfields. Advances in Experimental Medicine and Biology has been publishing exceptionalworksinthefieldforover40years,andisindexedinSCOPUS, Medline (PubMed), Journal Citation Reports/Science Edition, Science Cita- tion Index Expanded (SciSearch, Web of Science), EMBASE, BIOSIS, Reaxys, EMBiology, the Chemical Abstracts Service (CAS), and Pathway Studio. 2020ImpactFactor:2.622 Moreinformationaboutthisseriesathttps://link.springer.com/bookseries/5584 (cid:129) Shibo Jiang Lu Lu Editors Virus Entry Inhibitors Stopping the Enemy at the Gate Editors ShiboJiang LuLu KeyLaboratoryofMedicalMolecular KeyLaboratoryofMedicalMolecular Virology(MOE/NHC/CAMS) Virology(MOE/NHC/CAMS) SchoolofBasicMedical SchoolofBasicMedical Sciences,InstituteofInfectiousDisease Sciences,InstituteofInfectiousDisease andBiosecurity,FudanUniversity andBiosecurity,FudanUniversity Shanghai,China Shanghai,China ISSN0065-2598 ISSN2214-8019 (electronic) AdvancesinExperimentalMedicineandBiology ISBN978-981-16-8701-3 ISBN978-981-16-8702-0 (eBook) https://doi.org/10.1007/978-981-16-8702-0 #SpringerNatureSingaporePteLtd.2022 Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeor part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway, andtransmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,or bysimilarordissimilarmethodologynowknownorhereafterdeveloped. Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthis publication does not imply, even in the absence of a specific statement, that such names are exemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse. Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthis bookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernorthe authorsortheeditorsgiveawarranty,expressedorimplied,withrespecttothematerialcontained hereinorforanyerrorsoromissionsthatmayhavebeenmade.Thepublisherremainsneutralwith regardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations. ThisSpringerimprintispublishedbytheregisteredcompanySpringerNatureSingaporePteLtd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721,Singapore Preface Virusentryintothehosttargetcellisthefirststepoftheviralreplicationcycle. It isinitiatedbytheattachmentoftheviral particle tothetargetcellthrough specificinteractionbetweentheviralsurfaceprotein(s)andreceptor(s)onthe host cell. This interaction triggers the conformation changes of the viral surface protein(s), resulting in entry, via membrane fusion or endocytosis, oftheviralgeneticmaterialsintothehostcellforreplication. Virusentryinhibitorsareantiviralagentsthatblockviralentryintothehost cell,includingthosethatbindviralsurfaceproteins,interferewithinteraction between viral and host proteins, inhibit viral protein-mediated plasma or endosomalmembranefusion,orinactivatecell-freevirions. In the early 1990s, Jiang and colleagues identified the first highly potent humanimmunodeficiencyvirus(HIV)entryinhibitorderivedfromtheHIV-1 gp41 C-terminal heptad repeat (CHR) domain and the related patent was licensed to Trimeris, Inc., which jointly with Roche Pharmaceuticals devel- oped the first virus entry inhibitor-based anti-HIV peptide drug, enfuvirtide (Fuzeon),approvedbytheUSFDAin2003.Sincethen,severalseriesofthe smallmolecule-,peptide-,andprotein-basedvirusentryinhibitorshavebeen orarebeingdevelopedagainstenvelopedviruses,includinghumanimmuno- deficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), severeacuterespiratorysyndromecoronavirus2(SARS-CoV-2),Ebolavirus (EBOV), Hendra virus (HeV), Nipah virus (NiV), influenza virus (IFV), parainfluenzavirus(PIV),Zikavirus(ZIKV),Denguevirus(DENV),hepati- tis Cvirus (HCV),andhepatitis Bvirus (HBV),andnon-enveloped viruses, such as human papillomavirus (HPV). Since many of these viruses, such as SARS-CoV, SARS-CoV-2, EBOV, ZIKV, HeV, and NiV, can cause outbreaks of highly pathogenic emerging infectious diseases, virus entry inhibitorsagainsttheseviruseshavegreatpotentialtobeusedforthepreven- tionandtreatmentoftheseinfectiousdiseases. Inthisbook,wewilldiscusstheadvancesintheresearchanddevelopment ofthesmallmolecule-,peptide-,andprotein-basedvirusentryinhibitorsasa novel class of antiviral drugs for the treatment and prevention of viral infection. Theoretically, virus neutralizing antibodies should belong to the protein- based virus entry inhibitors since they can neutralize viral infection by blocking virus attachment to the receptor on the host cell, interfering with v vi Preface virus-cell fusion or inhibiting virus entry into the host cell for replication. Since several books about the viral neutralizing antibodies have been published by Springer, this book contains no chapter mainly discussing the viralneutralizingantibodies. Many authorsfor thisbookareinthetoplistoftheexperts worldwidein the fields of HIV fusion inhibitors (https://expertscape.com/ex/hiv+fusion +inhibitors)andviralfusionproteins(http://expertscape.com/ex/viral+fusion +proteins). Weheartilyappreciatealltheauthorsfortheircontributionstothisbook. Shanghai,China ShiboJiang Shanghai,China LuLu Acknowledgments WewouldliketoacknowledgethesupportfromMs.LinXuattheSchoolof Basic Medical Sciences, Fudan University, who provided project manage- mentandeditorialsupporttobotheditorsandallthecontributingauthors. Wealsoacknowledgethecontributionofallourpreviousandcurrentteam members and colleagues to the research and development of virus entry inhibitors at the New York Blood Center, including Drs. Li Zhang, Qian Zhao,HongLu,WeiguoJing,XuxiaYan,XiaozhiLu,ShuwenLiu,Yuxian He, Lanying Du, Chungen Pan, Yuan Shui, Zhi Qi, Dongmei Cai, Xi Chen, Xiaowen Yu, Xiujuan Zhang, Zhonghua Liu, Lifeng Cai, Lin Li, Suiyi Tan, JieYang,CuiqingMa,NaruZhang,ChenglaiXia,TongXiang,WanboTai, Yaning Gao, Dong Zhu, Ye Li, Jan Tang, A. Robert Neurath, Asim K.Debnath,JinkuiNiu,andJamesFarmar;andthoseattheFudanUniversity, includingDrs.QianWang,WeiXu, LingXu, ShuaiXia,ShanSu,Zezhong Liu,FeiYu,QiLiu,ZhiwuSun,BiaoHe,WenLi,HaoyangLi,YufengYu, QianqianQi,PeiyuLi,YuMeng,WenwenBi,YuhongFu,CongWang,Lulu Si, Xiaojie Zhu, Yanyan Dai, Wenqian Yang, Chen Hua, Yuchen Qu, Miao Cao,JiayiTang,XinlingWang,YanxingCai,JingPu,XiaojieSu,Qiaoshuai Lan, Jie Zhou, Lijue Wang, Qianyu Duan, Najing Cao, Lixiao Xing, Fanke Jiao,TianyuLu,TianleiYing,JingheHuang,QiaoWang,andYouhuaXie. Wethankourcollaboratorswhomakecontributiontothestudiesonvirus entryinhibitors,includingDrs.YinghuaChen,JiWang,PeiTong,Xiaowen Yu, Yun Zhu, Hengwen Yang, Peng Zuo, and Fan Wu at Tsinghua Univer- sity; Drs. Keliang Liu, Lan Xie, Song Li, Xiaoyang He, Weiguo Shi, Qiyan Jia,andChaoWangattheBeijingInstituteofPharmacologyandToxicology; Drs. Qiuyun Dai and Mingxing Dong at the Beijing Institute of Biotechnol- ogy;Drs.YusenZhou,GuangjieZhao,ShihuiSun,andChengfengQinatthe Beijing Institute of Microbiology and Epidemiology; Drs. Shuguang Wu, Ruitao Zhang, Xiaoning Yu, Haitao Wang, Jiping Shao, and Jiayin Qiu at the Southern Medical University; Drs. Bojian Zheng, Kwok-Yung Yuen, Jasper Fuk-Woo Chan, Hanjun Zhao, Shuofeng Yuan, Jie Zhou, Kelvin K. W. To, and Richard Kao at the University of Hong Kong; Drs. Gengfu Xiao, Zhengli Shi, Huiming Yan, and Xi Zhou at the Wuhan Institute of Microbiology;Drs.YimingShaoandLiyingMaatChinaCDC;andDrs.Min Lu, Yichiel Shai, Andrew D. Hamilton, Justin T Ernst, Jianfeng Cai, Frank Kirchhoff, Jan Münch, Zhikai Xu, Dominique Schols, Erik De Clercq, vii viii Acknowledgments DimiterS Dimitrov,Robert Blumenthal,Carol D.Weiss,Ding-KwoChang, YunLiao,LaixiWang,PoTian,YibangChen,CarlosREscalante,Chien-Te K.Tseng,Zhi-hongJiang,andAlanRKatritzky. Contents 1 VirusEntryInhibitors:Past,Present,andFuture. . . . . . . 1 ShanSu,WeiXu,andShiboJiang 2 Peptide-BasedHIVEntryInhibitors. . . . . . . . . . . . . . . . . 15 JingPu,QianWang,andShiboJiang 3 Small-MoleculeHIVEntryInhibitorsTargeting gp120andgp41. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 FeiYuandShiboJiang 4 TheGenesisandFutureProspectsofSmallMolecule HIV-1AttachmentInhibitors. . . . . . . . . . . . . . . . . . . . . . . 45 TaoWang,JohnF.Kadow,NicholasA.Meanwell, andMarkKrystal 5 EndogenousPeptideInhibitorsofHIVEntry. . . . . . . . . . 65 MirjaHarms,ManuelHayn,FabianZech,FrankKirchhoff, andJanMünch 6 Peptide-BasedDualHIVandCoronavirusEntry Inhibitors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 HuanWangandChaoWang 7 CoronavirusEntryInhibitors. . . . . . . . . . . . . . . . . . . . . . 101 QiaoshuaiLan,ShuaiXia,andLuLu 8 InfluenzaVirusEntryinhibitors. . . . . . . . . . . . . . . . . . . . 123 JieYangandShuwenLiu 9 Broad-spectrumRespiratoryVirusEntryInhibitors. . . . . 137 HanjunZhaoandKwok-YungYuen 10 EbolaVirusEntryInhibitors. . . . . . . . . . . . . . . . . . . . . . . 155 RuikunDu,QinghuaCui,MichaelCaffrey,andLijunRong 11 FlavivirusEntryInhibitors. . . . . . . . . . . . . . . . . . . . . . . . 171 YufengYu,LuluSi,andYuMeng 12 EntryInhibitorsofHepatitisBandDViruses. . . . . . . . . . 199 YangYangandYouhuaXie ix