Progress in Developing Inhibitors of SARS-CoV-2 3C-Like Protease

Abstract

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The viral outbreak started in late 2019 and rapidly became a serious health threat to the global population. COVID-19 was declared a pandemic by the World Health Organization in March 2020. Several therapeutic options have been adopted to prevent the spread of the virus. Although vaccines have been developed, antivirals are still needed to combat the infection of this virus. SARS-CoV-2 is an enveloped virus, and its genome encodes polyproteins that can be processed into structural and nonstructural proteins. Maturation of viral proteins requires cleavages by proteases. Therefore, the main protease (3 chymotrypsin-like protease (3CLpro) or Mpro) encoded by the viral genome is an attractive drug target because it plays an important role in cleaving viral polyproteins into functional proteins. Inhibiting this enzyme is an efficient strategy to block viral replication. Structural studies provide valuable insight into the function of this protease and structural basis for rational inhibitor design. In this review, we describe structural studies on the main protease of SARS-CoV-2. The strategies applied in developing inhibitors of the main protease of SARS-CoV-2 and currently available protein inhibitors are summarized. Due to the availability of high-resolution structures, structure-guided drug design will play an important role in developing antivirals. The availability of high-resolution structures, potent peptidic inhibitors, and diverse compound scaffolds indicate the feasibility of developing potent protease inhibitors as antivirals for COVID-19.

Biflavonoids from Rhus succedanea as probable natural inhibitors against SARS-CoV-2: a molecular docking and molecular dynamics approach

“…This protease has 11 putative cleavage positions indicating its prevalence in proteolytic processing (Yang et al, 2003 ; Zhang et al., 2020 ). The Mpro has been found as a potential target to design and developing drugs against SARS-CoV-2 (Amin et al., 2020 ; Amin & Jha, 2020 ; Enmozhi et al., 2020 ; Ghosh et al., 2020 ; Goyal & Goyal, 2020 ; Li & Kang, 2020 ; Ullrich & Nitsche, 2020 ; ) since very little similarity with human proteases makes the drugs less toxic to humans (Anand et al., 2002 ; Joshi et al., 2020 ). Therefore, finding promising natural inhibitors for the Mpro can hinder the SARS-CoV-2 virus replication in the host cell and reduce its infectivity (Havranek & Islam, 2020 ; Dong & Gao, 2020 ).…”

Detecting SARS-CoV-2 3CLpro expression and activity using a polyclonal antiserum and a luciferase-based biosensor

“…We describe a luciferase-based biosensor assay for evaluating small molecule inhibitors of SARS-CoV-2 3CLpro. Several protease inhibitors have recently been reported to inhibit the replication of SARS-CoV-2 in cell culture ( He et al, 2020 ; Li and Kang, 2020 ). However, for these compounds, it remains to be determined if they exert their antiviral activity by inhibiting a viral or a host protease.…”

“…Thus, there is a need to develop strategies to identify inhibitors that block highly conserved viral proteins essential for virus replication. The coronavirus 3C-like protease (3CLpro, also termed main protease, Mpro) is such a target ( He et al, 2020 ; Li and Kang, 2020 ). This protease cleaves the replicase polyprotein at 11 sites, and this processing is required to generate a functional replicase complex.…”

Medicinal Plants as Recent Complementary and Alternative Therapy for COVID-19: A Review

“…8 The pp1a and pp1ab by 3-chymotrypsin-like protease (3CLpro) and papain-like protease (PL) proteases were cleaved to produce 16 nonstructural proteins. 9,10 During the viral maturation process, coronaviruses encode papain-like protease (PLP) and 3CLPro proteases. 6,11 Therefore the 3CLPro protease from SARS-CoV determined as essential target for the discovery of SARS-CoV drugs.…”