Background: COVID-19 is still causing long-term health consequences, mass deaths, and collapsing healthcare systems around the world. There are no efficient drugs for its treatment. However, previous studies revealed that SARS-CoV-2 and SARS-CoV have 96% and 86.5% similarities in cysteine proteases (3CL^pro) and papain-like protease (PL^pro) sequences, respectively. This resemblance could be important in the search for drug candidates with antiviral effects against SARS-CoV-2.

Objective: This paper is a compilation of natural products that inhibit SARS-CoV 3CL^pro and PL^pro and, concomitantly, reduce inflammation and/or modulate the immune system as a perspective strategy for COVID-19 drug discovery. It also presents in silico studies performed on these selected natural products using SARS-CoV-2 3CL^pro and PL^pro as targets to propose a list of hit compounds.

Methods: The plant metabolites were selected in the literature based on their biological activities on SARS-CoV proteins, inflammatory mediators, and immune response. The consensus docking analysis was performed using four different packages.

Results: Seventy-nine compounds reported in the literature with inhibitory effects on SARS-CoV proteins were reported as anti-inflammatory agents. Fourteen of them showed immunomodulatory effects in previous studies. Five and six of these compounds showed significant in silico consensus as drug candidates that can inhibit PL^pro and 3CL^pro, respectively. Our findings corroborated recent results reported on anti-SARS-CoV-2 in the literature.

Conclusion: This study revealed that amentoflavone, rubranoside B, savinin, psoralidin, hirsutenone, and papyriflavonol A are good drug candidates for the search of antibiotics against COVID-19.