Helicase (nsp13) as a Target to Develop Inhibitors for Combating SARS-CoV-2 Infection

Abstract

<p> The COVID-19 pandemic caused by the SARS-CoV-2 remains a global public health crisis. An effective way to fight against COVID-19 is a vaccine plus a drug (via oral administration). Identification of proteins that is critical for virus replication will provide guidance for searching drugs quickly¹. SARS-CoV-2 genome encodes 16 non-structural proteins with multiple enzymatic functions². Among them, metalloenzymes are crucial for the virulence and replication of virus and are the potential targets. Nsp13 (i.e. helicase) is considering as a promising drug target due to its unique structure and function³. It consists of zinc-finger domain, stalk domain, 1B domain, 1A domain and 2A domain, possessing the RNA helicase and ATPase activities.<br></p><p>Historically, metal compounds have been used as antimicrobial agents, but their antiviral activities have rarely been explored. Previously, we found that bismuth citrate-containing drugs and other bismuth-based complexes exhibited inhibition towards both the ATPase and DNA-unwinding activities of the SARS-CoV-2 helicase via an irreversible displacement of Zn(II) from the enzyme by Bi(III), highlighting nsp13, a perfect target for anti-coronavirus drugs and the clinical potential of Bi(III) drugs or other metallodrugs for the treatment of COVID-19 . Here, we report discovery of potent inhibitors targeting helicase among a battery of metallodrugs (i.e. Bi(III)- and Au(I)-containing drugs). We subsequently examined their mode of inhibition, validated in vivo activity in hamsters. We aim to develop a more effective antiviral drug to combat COVID-19 disease based on the nsp13.</p>