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PLoS Biol. 2019 Jun 11;17(6):e3000281. doi: 10.1371/journal.pbio.3000281. eCollection 2019 Jun.

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

Author information

1
Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
2
Faculty of Biological and Environmental Sciences, Molecular and Integrative Bioscience Research Programme, University of Helsinki, Helsinki, Finland.
3
Helsinki Institute of Life Sciences, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
4
Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India.

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.

Conflict of interest statement

The authors have declared that no competing interests exist.

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