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.
Highlights
Rhino- and enteroviruses are important human pathogens
We propose that this pocket is crucial for conformational changes required for viral RNA release, and we describe a class of compounds targeting this pocket with broad-spectrum activity against entero-/rhinoviruses
The antiviral activity of compound 17 was further confirmed in a virus yield assay in which it reduced, in a dosedependent manner, the production of Coxsackievirus B3 (CVB3) RNA and CVB3 infectious virus particles with 50% effective concentration (EC50) values of 0.4 ± 0.01 μM and 1.1 ± 0.3 μM, respectively (Fig 1C)
Summary
Rhino- and enteroviruses (family Picornaviridae) are important human pathogens. Rhinoviruses are responsible for the common cold and are the most important trigger of exacerbations of asthma and chronic obstructive pulmonary disease (COPD) [1]. Millions of people are affected by enteroviruses; there are 29 Coxsackieviruses, 28 echoviruses, and 5 other enteroviruses that cause disease (such as hand, foot and mouth disease, myocarditis, pancreatitis, aseptic meningitis, and encephalitis) in man [2]. Massive outbreaks of the enterovirus 71 (EVA71) occurred in Asia that left a large number of children with life-.
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