Inhibitory effect of phytochemicals on SARS-CoV-2 PLpro proteolytic and deubiquitinase activity

Date of Award

5-2022

Degree Type

Thesis

Degree Name

Master of Science in Biomedical Sciences

First Advisor

Shashidharamurthy Taval, PhD

Second Advisor

Srujana Rayalam, DVM, PhD

Third Advisor

Vicky Mody, PhD

Fourth Advisor

Bonnie Buxton, Ph.D.

Fifth Advisor

Lori Redmond, Ph.D.

Abstract

The surge of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes the disease known as COVID-19, is a global threat due to its transmission rate, especially with newly emerging variants. Although vaccines are available, infections still occur as new mutants arise, indicating the necessity for an updated vaccine. Currently, only two new FDA-approved antiviral drugs are available to treat SARS-CoV-2 infection, but their side effects are of concern. Therefore, it is crucial to develop the potential therapeutics to prevent the viral spread of SARS-CoV-2. Recent studies have shown that RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro), and Papain-like protease (PLpro) are necessary for coronaviruses' replication. Among these three enzymes, PLpro exhibits both proteolytic and deubiquitinase (DUB) activity and is responsible for disrupting the host's innate immune response against SARS-CoV-2. Because of this unique property of PLpro, we investigated the inhibitory effects of phytochemicals, natural compounds isolated from vegetables, fruits, and plants, on the SARS-CoV-2 PLpro enzyme. Our data indicate that the phytochemicals such as Myricetin (nuts, berries, and red wine) and Theaflavin (black tea) exhibited more than 80% inhibition of both proteolytic and DUB activity at 50 μM concentrations. In comparison, γ-mangostin (mangosteen), rutin (buckwheat), quercetin (onions), and mangiferin (mangoes) showed 60-70% inhibitory activity at higher concentrations (100 and 200 μM). Our data indicate that the phytochemicals mentioned above inhibit the proteolytic and DUB activity of SARS-Cov-2 PLpro, thus preventing viral replication and promoting host innate immune response. However, the therapeutic potential of these phytochemicals needs to be validated by pre-clinical and clinical studies.

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