Inhibitory effect of phytochemicals towards SARS-CoV-2 papain like protease (PLpro) proteolytic and deubiquitinase activity

Authors

Anasha Kawall, Philadelphia College of Osteopathic Medicine
Devin S M Lewis, Philadelphia College of Osteopathic Medicine
Avini Sharma, Philadelphia College of Osteopathic Medicine
Krishna Chavada, Philadelphia College of Osteopathic Medicine
Rahul Deshmukh
Srujana Rayalam, Philadelphia College of Osteopathic MedicineFollow
Vicky Mody, Philadelphia College of Osteopathic MedicineFollow
Shashidharamurthy Taval, Philadelphia College of Osteopathic MedicineFollow

Document Type

Article

Publication Date

1-1-2022

Abstract

Recent studies have shown that RNA-dependent RNA polymerase (RdRp), 3-chymotrypsin-like protease (3CLpro), and papain-like protease (PLpro) are necessary for SARS-CoV-2 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 on the SARS-CoV-2 PLpro enzyme. Our data indicates that the phytochemicals such as catechin, epigallocatechin gallate (EGCG), mangiferin, myricetin, rutin, and theaflavin exhibited inhibitory activity with IC₅₀ values of 14.2, 128.4, 95.3, 12.1, and 43.4, and 7.3 μM, respectively, towards PLpro proteolytic activity. However, the IC50 values of quercetin, oleuropein, and γ-mangostin are ambiguous. We observed that EGCG, mangiferin, myricetin, oleuropein, rutin, and theaflavin have also inhibited the DUB activity with IC₅₀ values of 44.7, 104.3, 29.2, 131.5, 61.7, and 13.2 μM, respectively. Mechanistically, the ligand-protein interaction structural modeling suggests that mangiferin, EGCG, theaflavin, and oleuropein shows that these four ligands interact with Glu¹⁶⁷, and Tyr²⁶⁸, however mangiferin and oleuropein showed very weak interaction with Glu¹⁶⁷ as compared to EGCG, and theaflavin which reflects their low IC₅₀ values for DUB activity. 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.

Publication Title

Frontiers in Chemistry

Volume

10

First Page

1100460

Last Page

1100460

PubMed ID

36712981

Comments

This article was published in Frontiers in Chemistry.

The published version is available at https://doi.org/10.3389/fchem.2022.1100460.

Copyright © 2023 Kawall, Lewis, Sharma, Chavada, Deshmukh, Rayalam, Mody and Taval. CC BY 4.0.

Recommended Citation

Kawall, Anasha; Lewis, Devin S M; Sharma, Avini; Chavada, Krishna; Deshmukh, Rahul; Rayalam, Srujana; Mody, Vicky; and Taval, Shashidharamurthy, "Inhibitory effect of phytochemicals towards SARS-CoV-2 papain like protease (PLpro) proteolytic and deubiquitinase activity" (2022). PCOM Scholarly Works. 2182.
https://digitalcommons.pcom.edu/scholarly_papers/2182