| Title | A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses. | ||
| Author | 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 | ||
| Journal | PLoS Biol | Publication Year/Month | 2019-Jun |
| PMID | 31185007 | PMCID | PMC6559632 |
| Affiliation + expend | 1.Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium. | ||
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.