Virus structure and structure-based antivirals

Structure-based antiviral developments in the past two years have been dominated by the structure determination and inhibition of SARS-CoV-2 proteins and new lead molecules for picornaviruses. The SARS-CoV-2 spike protein has been targeted successfully with antibodies, nanobodies, and receptor protein mimics effectively blocking receptor binding or fusion. The two most promising non-structural proteins sharing strong structural and functional conservation across virus families are the main protease and the RNA-dependent RNA polymerase, for which design and reuse of broad range inhibitors already approved for use has been an attractive avenue. For picornaviruses, the increasing recognition of the transient expansion of the capsid as a critical transition towards RNA release has been targeted through a newly identified, apparently widely conserved, druggable, interprotomer pocket preventing viral entry. We summarize some of the key papers in these areas and ponder the practical uses and contributions of molecular modeling alongside empirical structure determination.

Automated summary

Over the past two years, structure-based antiviral developments have focused on determining the structures and inhibiting SARS-CoV-2 proteins and picornaviruses, leading to the discovery of new potential drugs such as nanobodies and receptor protein mimics. Targeting the spike protein of SARS-CoV-2 and conserved non-structural proteins like the main protease and RNA-dependent RNA polymerase has shown promise, with design and reuse of broad range inhibitors being an attractive avenue. Recognizing the critical role of capsid expansion in picornaviruses, researchers have identified a druggable interprotomer pocket to prevent viral entry.