A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses

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dc.contributor.author Abdelnabi, Rana
dc.contributor.author Geraets, James A.
dc.contributor.author Ma, Yipeng
dc.contributor.author Mirabelli, Carmen
dc.contributor.author Flatt, Justin W.
dc.contributor.author Domanska, Ausra
dc.contributor.author Delang, Leen
dc.contributor.author Jochmans, Dirk
dc.contributor.author Kumar, Timiri Ajay
dc.contributor.author Jayaprakash, Venkatesan
dc.contributor.author Sinha, Barij Nayan
dc.contributor.author Leyssen, Pieter
dc.contributor.author Butcher, Sarah J.
dc.contributor.author Neyts, Johan
dc.date.accessioned 2019-07-31T11:49:02Z
dc.date.available 2019-07-31T11:49:02Z
dc.date.issued 2019-06
dc.identifier.citation Abdelnabi , R , Geraets , J A , Ma , Y , Mirabelli , C , Flatt , J W , Domanska , A , Delang , L , Jochmans , D , Kumar , T A , Jayaprakash , V , Sinha , B N , Leyssen , P , Butcher , S J & Neyts , J 2019 , ' A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses ' , PLoS Biology , vol. 17 , no. 6 , 3000281 . https://doi.org/10.1371/journal.pbio.3000281
dc.identifier.other PURE: 125904552
dc.identifier.other PURE UUID: fbfe2932-a252-48b4-87be-5ec0d4ab4a6b
dc.identifier.other WOS: 000473675900013
dc.identifier.other ORCID: /0000-0002-3772-6003/work/60160917
dc.identifier.other ORCID: /0000-0001-7060-5871/work/60161328
dc.identifier.other ORCID: /0000-0003-3378-0683/work/60162920
dc.identifier.other ORCID: /0000-0001-5406-8156/work/60163200
dc.identifier.uri http://hdl.handle.net/10138/304093
dc.description.abstract Rhino- and enteroviruses are important human pathogens, against which no antivirals are available. The best-studied inhibitors are capsid binders that fit in a hydrophobic pocket of the viral capsid. Employing a new class of entero-/rhinovirus inhibitors and by means of cryo-electron microscopy (EM), followed by resistance selection and reverse genetics, we discovered a hitherto unknown druggable pocket that is formed by viral proteins VP1 and VP3 and that is conserved across entero-/rhinovirus species. We propose that these inhibitors stabilize a key region of the virion, thereby preventing the conformational expansion needed for viral RNA release. A medicinal chemistry effort resulted in the identification of analogues targeting this pocket with broad-spectrum activity against Coxsackieviruses B (CVBs) and compounds with activity against enteroviruses (EV) of groups C and D, and even rhinoviruses (RV). Our findings provide novel insights in the biology of the entry of entero-/rhinoviruses and open new avenues for the design of broad-spectrum antivirals against these pathogens. en
dc.format.extent 17
dc.language.iso eng
dc.relation.ispartof PLoS Biology
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject INHIBITOR
dc.subject PROTEIN
dc.subject REPLICATION
dc.subject 1182 Biochemistry, cell and molecular biology
dc.title A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses en
dc.type Article
dc.contributor.organization Molecular and Integrative Biosciences Research Programme
dc.contributor.organization Macromolecular structure and function
dc.contributor.organization Institute of Biotechnology
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1371/journal.pbio.3000281
dc.relation.issn 1544-9173
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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