Journal Article

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

Abdelnabi, Rana, Leyssen, Pieter, Butcher, Sarah J., Kumar, Timiri Ajay, Jayaprakash, Venkatesan, Geraets, James A., Sinha, Barij Nayan, Jochmans, Dirk, Flatt, Justin W., Neyts, Johan, Delang, Leen, Domanska, Aušra, Ma, Yipeng, Mirabelli, Carmen

2019

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Amino Acid Sequence - genetics / Amino Acids - genetics / Antigens, Viral / Antimicrobial agents / Antiviral Agents / Asthma / Automation / Binders / Binding Sites / Biology and Life Sciences / Biotechnology / Capsid - drug effects / Capsid - metabolism / Capsid - ultrastructure / Capsid Proteins - metabolism / Capsid Proteins - ultrastructure / Chemotherapy / Chronic obstructive pulmonary disease / Cryoelectron Microscopy - methods / Drug Development - methods / Drug resistance / Electron microscopy / Encephalitis / Enterovirus - drug effects / Enterovirus - ultrastructure / Enteroviruses / Environmental science / Funding / Genetics / Health aspects / Humans / Hydrophobicity / Immunology / Infections / Inhibitors / Laboratories / Life sciences / Medical research / Medicine and Health Sciences / Microscopy / Models, Molecular / Molecular Conformation / Organic chemistry / Pathogens / Pharmaceutical sciences / Poliomyelitis / Proteins / Research and Analysis Methods / Rhinovirus / Rhinovirus - drug effects / Rhinovirus - ultrastructure / Ribonucleic acid / RNA / Supervision / Vaccines / Viral Proteins - chemistry / Viral Proteins - ultrastructure / Virion - genetics / Virions / Virology / Viruses / VP1 protein / VP3 protein