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

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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

Titel: A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses
Författare: Abdelnabi, Rana; Geraets, James A.; Ma, Yipeng; Mirabelli, Carmen; Flatt, Justin W.; Domanska, Ausra; Delang, Leen; Jochmans, Dirk; Kumar, Timiri Ajay; Jayaprakash, Venkatesan; Sinha, Barij Nayan; Leyssen, Pieter; Butcher, Sarah J.; Neyts, Johan
Upphovmannens organisation: Molecular and Integrative Biosciences Research Programme
Macromolecular structure and function
Institute of Biotechnology
Datum: 2019-06
Språk: eng
Sidantal: 17
Tillhör serie: PLoS Biology
ISSN: 1544-9173
DOI: https://doi.org/10.1371/journal.pbio.3000281
Permanenta länken (URI): http://hdl.handle.net/10138/304093
Abstrakt: 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.
Subject: COXSACKIEVIRUS B3
INHIBITOR
PROTEIN
REPLICATION
1182 Biochemistry, cell and molecular biology
Referentgranskad: Ja
Licens: cc_by
Användningsbegränsning: openAccess
Parallelpublicerad version: publishedVersion


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