Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19
Remarkably, both ebselen and disulfiram are currently under evaluation in phase II clinical trials for the treatment of COVID-19 (NCT04484025 and NCT04485130). Taken together, these data strongly support the clinical potential of these drugs to treat COVID-19.
Recent Progress in the Drug Development Targeting SARS-CoV-2 Main Protease as Treatment for COVID-19
The sudden outbreak of 2019 novel coronavirus (2019-nCoV, later named SARS-CoV-2) rapidly turned into an unprecedented pandemic of coronavirus disease 2019 (COVID-19). This global healthcare emergency marked the third occurrence of a deadly coronavirus (CoV) into the human society after entering the new millennium, which overwhelmed the worldwide healthcare system and affected the global economy. However, therapeutic options for COVID-19 are still very limited. Developing drugs targeting vital proteins in viral life cycle is a feasible approach to overcome this dilemma. Main protease (Mpro) plays a dominant role in processing CoV-encoded polyproteins which mediate the assembly of replication-transcription machinery and is thus recognized as an ideal antiviral target. Here we summarize the recent progress in the discovery of anti-SARS-CoV-2 agents against Mpro. Combining structural study, virtual screen, and experimental screen, numerous therapeutic candidates including repurposed drugs and ab initio designed compounds have been proposed. Such collaborative effort from the scientific community would accelerate the pace of developing efficacious treatment for COVID-19.
Disulfiram is an FDA-approved drug for the treatment of alcohol dependence (Garbutt et al., 1999). It was also investigated as a repurposed drug for the treatment of cancers during the past few years (Skrott et al., 2017). It exhibited strong inhibition of Mpro activity against SARS-CoV-2 with an IC50 of 9.35 μM. Remarkably, both ebselen and disulfiram are currently under evaluation in phase II clinical trials for the treatment of COVID-19 (NCT04484025 and NCT04485130). Taken together, these data strongly support the clinical potential of these drugs to treat COVID-19.
Wen Cui1,2, Kailin Yang3* and Haitao Yang2,4 Front. Mol. Biosci., 04 December 2020