SARS-CoV-2 Protease Inhibitors of Natural Origin: Current Scenario and Future Prospects as Anti-COVID-19 Agents

COVID-19, an infectious disease caused by SARS-CoV-2, has impacted human lives since its first outbreak in China and became a pandemic within a short span. As on 20th April 2022, the WHO reported 504,079,039 confirmed COVID-19 cases and 6,204,155 deaths globally.

To combat COVID-19, a number of vaccination drives have been initiated, including vaccines such as Comirnaty and Spikevax approved by the FDA, while several others remain in the process of development or under emergency use authorization. On the other hand, Remdesivir, Baricitinib, in combination with Remdesivir, Paxlovid (Nirmatrelvir tablets and Ritonavir tablets, co-packaged for oral use), molnupiravir and monoclonal antibodies like Regen-COV (Casirivimab and Imdevimab combination), Sotrovimab, Bamlanivinab-Etesevimab combination are also approved for emergency use by US-FDA, but they have their own limitations.

In this view, four major target proteins of SARS-CoV-2 viz spike, envelop, membrane, nucleocapsid, have been identified for the design and discovery of new drug candidates. However, the main protease (Mpro) played a vital part in virus replication and transcription via extensive poly protein proteolysis. Thus, this has been considered as a promising therapeutic target.

In the search of new agents for COVID-19, natural products have also been explored, as they are one of valuable sources of therapeutic agents. Different plant-derived compounds, secondary metabolites, spices, honeybee constituents, lichen derivatives, and compounds of microbial and marine origins exhibiting vivid biological activities, have been reported to inhibit Mpro in in-silico studies. This chapter discusses and highlights the potential prospects of natural products, which can inhibit Mpro and might serve as drugs of the future or as leads for combating SARS-CoV-2.