Journal
VIROLOGY
Volume 562, Issue -, Pages 128-141Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.virol.2021.07.008
Keywords
Rhinovirus; Virus-host interaction; Cysteine proteinase; Fluoromethylketone inhibitor; Translation initiation; Anti-viral agent
Categories
Funding
- Austrian Science Fund [P-28183, W-1258]
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Members of the Picornavirus family can cause diseases in humans, with human rhinoviruses being the main causative agents of the common cold. Effective agents against rhinoviruses are necessary due to their role in increasing the severity of asthma and COPD. The 2A proteinase (2Apro) found in all enteroviruses is a potential target for drug development, with inactivating mutations resulting in a prevention of infectious virion assembly. Variations in sequence and substrate specificity between genetic groups A and B of RV 2Apro hinder their potential as drug targets.
Picornavirus family members cause disease in humans. Human rhinoviruses (RV), the main causative agents of the common cold, increase the severity of asthma and COPD; hence, effective agents against RVs are required. The 2A proteinase (2Apro), found in all enteroviruses, represents an attractive target; inactivating mutations in poliovirus 2Apro result in an extension of the VP1 protein preventing infectious virion assembly. Variations in sequence and substrate specificity on eIF4G isoforms between RV 2Apro of genetic groups A and B hinder 2Apro as drug targets. Here, we demonstrate that although RV-A2 and RV-B4 2Apro cleave the substrate GAB1 at different sites, the 2Apro from both groups cleave equally efficiently an artificial site containing P1 methionine. We determined the RV-A2 2Apro structure complexed with zVAM.fmk, containing P1 methionine. Analysis of this first 2Apro-inhibitor complex reveals a conserved hydrophobic P4 pocket among enteroviral 2Apro as a potential target for broad-spectrum anti-enteroviral inhibitors.
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