SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PLpro) mediates the cleavage of viral polyprotein and modulates the host’s innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PLpro inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PLpro inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PLpro inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PLpro inhibitors to the clinic.

Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

Endocrine-disrupting chemicals (EDCs) have significant impacts on biological systems, and have been shown to interfere with physiological systems, especially by disrupting the hormone balance. During the last few decades, EDCs have been shown to affect reproductive, neurological, and metabolic development and function and even stimulate tumor growth. EDC exposure during development can disrupt normal development patterns and alter susceptibility to disease. Many chemicals have endocrine-disrupting properties, including bisphenol A, organochlorines, polybrominated flame retardants, alkylphenols, and phthalates. These compounds have gradually been elucidated as risk factors for many diseases, such as reproductive, neural, and metabolic diseases and cancers. Endocrine disruption has been spread to wildlife and species that are connected to the food chains. Dietary uptake represents an important source of EDC exposure. Although EDCs represent a significant public health concern, the relationship and specific mechanism between EDCs and diseases remain unclear. This review focuses on the disease-EDC relationship and the disease endpoints associated with endocrine disruption for a better understanding of the relationship between EDCs-disease and elucidates the development of new prevention/treatment opportunities and screening methods.

/pdf/endocrine-disrupting-chemicals-and-disease-endpoints-1p9ngbd9.pdf

Endocrine-Disrupting Chemicals and Disease Endpoints

The devastating COVID-19 pandemic has caused more than six million deaths worldwide during the last 2 years. Effective therapeutic agents are greatly needed, yet promising magic bullets still do not exist. Numerous natural products (cordycepin, gallinamide A, plitidepsin, telocinobufagin, and tylophorine) have been widely studied and play a potential function in treating COVID-19. In this paper, we reviewed published studies (from May 2021 to April 2022) relating closely to bioactive natural products (isolated from medicinal plants, animals products, and marine organisms) in COVID-19 therapy in vitro to provide some essential guidance for anti-SARS-CoV-2 drug research and development.

Bioactive natural products in COVID-19 therapy

Abstract SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host’s innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections. 

/pdf/antiviral-activity-of-natural-phenolic-compounds-in-complex-25n803kp.pdf

Antiviral activity of natural phenolic compounds in complex at an allosteric site of SARS-CoV-2 papain-like protease

https://doi.org/10.1016/j.mam.2022.101151

Protein structure-based in-silico approaches to drug discovery: Guide to COVID-19 therapeutics

The most common host entry point of human adapted coronaviruses (CoV) including SARS-CoV-2 is through the initial colonization in the nostril and mouth region which is responsible for spread of the infection. Most recent studies suggest that the commercially available oral and nasal rinse products are effective in inhibiting the viral replication. However, the anti-viral mechanism of the active ingredients present in the oral rinses have not been studied. In the present study, we have assessed in vitro enzymatic inhibitory activity of active ingredients in the oral mouth rinse products: aloin A and B, chlorhexidine, eucalyptol, hexetidine, menthol, triclosan, methyl salicylate, sodium fluoride and povidone, against two important proteases of SARS-CoV-2 PLpro and 3CLpro. Our results indicate only aloin A and B effectively inhibited proteolytic activity of PLpro with an IC50 of 13.16 and 16.08 μM. Interestingly, neither of the aloin isoforms inhibited 3CLpro enzymatic activity. Computational structural modelling of aloin A and B interaction with PLpro revealed that, both aloin isoforms form hydrogen bond with Tyr268 of PLpro, which is critical for their proteolytic activity. Furthermore, 100 ns molecular dynamics (MD) simulation studies predicted that both aloin isoforms have strong interaction with Glu167, which is required for PLpro deubiquitination activity. Our results from the in vitro deubiquitinase inhibition assay show that aloin A and B isomers exhibit deubiquitination inhibitory activity with an IC50 value of 15.68 and 17.51 µM, respectively. In conclusion, the isoforms of aloin inhibit both proteolytic and the deubiquitinating activity of SARS-CoV-2 PLpro, suggesting potential in inhibiting the replication of SARS-CoV-2 virus. 

/pdf/aloin-isoforms-a-and-b-selectively-inhibits-proteolytic-and-3qt1vvlv.pdf

Aloin isoforms (A and B) selectively inhibits proteolytic and deubiquitinating activity of papain like protease (PLpro) of SARS-CoV-2 in vitro

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. Graphical Abstract Inhibition of proteolytic and deubiquitinase activity of SARS-CoV-2 PLpro enzyme by phytochemicals.

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

/pdf/aloin-isoforms-a-and-b-selectively-inhibits-proteolytic-and-pjuvhz1r.pdf

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Aloin isoforms (A and B) selectively inhibits proteolytic and deubiquitinating activity of papain like protease (PLpro) of SARS-CoV-2 in vitro

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

Aloin isoforms (A and B) selectively inhibits proteolytic and deubiquitinating activity of papain like protease (PLpro) of SARS-CoV-2 in vitro