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

DOI: 10.1371/journal.pbio.3000281 DOI Help

Authors: Rana Abdelnabi (KU Leuven) , James A. Geraets (University of Helsinki) , Yipeng Ma (KU Leuven) , Carmen Mirabelli (KU Leuven) , Justin W. Flatt (University of Helsinki) , Ausra Domanska (University of Helsinki) , Leen Delang (KU Leuven) , Dirk Jochmans (KU Leuven) , Timiri Ajay Kumar (Birla Institute of Technology) , Venkatesan Jayaprakash (Birla Institute of Technology) , Barij Nayan Sinha (Birla Institute of Technology) , Pieter Leyssen (KU Leuven) , Sarah Butcher (University of Helsinki) , Johan Neyts (KU Leuven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Biology

State: Published (Approved)
Published: June 2019
Diamond Proposal Number(s): 1973

Open Access Open Access

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.

Journal Keywords: Antivirals; Coxsackieviruses; Viral packaging; Rhinovirus infection; Electron cryo-microscopy; Enteroviruses; Antimicrobial resistance; Virions

Diamond Keywords: Viruses

Subject Areas: Biology and Bio-materials, Medicine

Diamond Offline Facilities: Electron Bio-Imaging Centre (eBIC)
Instruments: Krios I-Titan Krios I at Diamond

Added On: 18/06/2019 09:25

Documents:
nhh55.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Drug Discovery Infectious Diseases Pathogens Structural biology

Technical Tags:

Microscopy Electron Microscopy (EM) Cryo Electron Microscopy (Cryo EM)