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Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach.

ABSTRACT: In the current pandemic, finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inhibitors. We used the Informational spectrum method applied for Small Molecules for searching the Drugbank database followed by molecular docking. After in silico screening of drug space, we identified 44 drugs as potential SARS-CoV-2 PLpro inhibitors that we propose for further experimental testing.

SUBMITTER: Sencanski M

PROVIDER: S-EPMC8805381 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Identification of SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors Using Combined Computational Approach.

Sencanski Milan M Perovic Vladimir V Milicevic Jelena J Todorovic Tamara T Prodanovic Radivoje R Veljkovic Veljko V Paessler Slobodan S Glisic Sanja S

ChemistryOpen 20220201 2

In the current pandemic, finding an effective drug to prevent or treat the infection is the highest priority. A rapid and safe approach to counteract COVID-19 is in silico drug repurposing. The SARS-CoV-2 PLpro promotes viral replication and modulates the host immune system, resulting in inhibition of the host antiviral innate immune response, and therefore is an attractive drug target. In this study, we used a combined in silico virtual screening for candidates for SARS-CoV-2 PLpro protease inh ...[more]

PMID: 35103413

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Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2

Project description:The SARS-CoV-2 coronavirus encodes an essential papain-like protease domain as part of its non-structural protein (nsp)-3, namely SARS2 PLpro, that cleaves the viral polyprotein, but also removes ubiquitin-like ISG15 protein modifications as well as, with lower activity, Lys48-linked polyubiquitin. Structures of PLpro bound to ubiquitin and ISG15 reveal that the S1 ubiquitin binding site is responsible for high ISG15 activity, while the S2 binding site provides Lys48 chain specificity and cleavage efficiency. To identify PLpro inhibitors in a repurposing approach, screening of 3727 unique approved drugs and clinical compounds against SARS2 PLpro, identified no compounds that inhibited PLpro consistently or that could be validated in counterscreens. More promisingly, non-covalent small molecule SARS PLpro inhibitors also target SARS2 PLpro, prevent selfprocessing of nsp3 in cells, and display high potency and excellent antiviral activity in a SARS-CoV-2 infection model.

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Mechanism and inhibition of the papain-like protease, PLpro, of SARS-CoV-2.

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Non-Covalent Inhibitors of SARS-CoV-2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity.

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Mercapto-pyrimidines are reversible covalent inhibitors of the papain-like protease (PLpro) and inhibit SARS-CoV-2 (SCoV-2) replication.

Project description:The papain-like protease (PLpro) plays a critical role in SARS-CoV-2 (SCoV-2) pathogenesis and is essential for viral replication and for allowing the virus to evade the host immune response. Inhibitors of PLpro have great therapeutic potential, however, developing them has been challenging due to PLpro's restricted substrate binding pocket. In this report, we screened a 115 000-compound library for PLpro inhibitors and identified a new pharmacophore, based on a mercapto-pyrimidine fragment that is a reversible covalent inhibitor (RCI) of PLpro and inhibits viral replication in cells. Compound 5 had an IC50 of 5.1 μM for PLpro inhibition and hit optimization yielded a derivative with increased potency (IC50 0.85 μM, 6-fold higher). Activity based profiling of compound 5 demonstrated that it reacts with PLpro cysteines. We show here that compound 5 represents a new class of RCIs, which undergo an addition elimination reaction with cysteines in their target proteins. We further show that their reversibility is catalyzed by exogenous thiols and is dependent on the size of the incoming thiol. In contrast, traditional RCIs are all based upon the Michael addition reaction mechanism and their reversibility is base-catalyzed. We identify a new class of RCIs that introduces a more reactive warhead with a pronounced selectivity profile based on thiol ligand size. This could allow the expansion of RCI modality use towards a larger group of proteins important for human disease.

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Project description:SARS-CoV-2 proteases Mpro and PLpro are promising targets for antiviral drug development. In this study, we present an antiviral screening strategy involving a novel in-cell protease assay, antiviral and biochemical activity assessments, as well as structural determinations for rapid identification of protease inhibitors with low cytotoxicity. We identified eight compounds with anti-SARS-CoV-2 activity from a library of 64 repurposed drugs and modeled at protease active sites by in silico docking. We demonstrate that Sitagliptin and Daclatasvir inhibit PLpro, and MG-101, Lycorine HCl, and Nelfinavir mesylate inhibit Mpro of SARS-CoV-2. The X-ray crystal structure of Mpro in complex with MG-101 shows a covalent bond formation between the inhibitor and the active site Cys145 residue indicating its mechanism of inhibition is by blocking the substrate binding at the active site. Thus, we provide methods for rapid and effective screening and development of inhibitors for blocking virus polyprotein processing as SARS-CoV-2 antivirals. Additionally, we show that the combined inhibition of Mpro and PLpro is more effective in inhibiting SARS-CoV-2 and the delta variant.

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Identification of novel allosteric sites of SARS-CoV-2 papain-like protease (PLpro) for the development of COVID-19 antivirals.

Project description:Coronaviruses such as SARS-CoV-2 encode a conserved papain-like protease (PLpro) that is crucial for viral replication and immune evasion, making it a prime target for antiviral drug development. In this study, three surface pockets on SARS-CoV-2 PLpro that may function as sites for allosteric inhibition were computationally identified. To evaluate the effects of these pockets on proteolytic activity, 52 residues were separately mutated to alanine. In Pocket 1, located between the Ubl and thumb domains, the introduction of alanine at T10, D12, T54, Y72, or Y83 reduced PLpro activity to <12% of that of WT. In Pocket 2, situated at the interface of the thumb, fingers, and palm domains, Q237A, S239A, H275A, and S278A inactivated PLpro. Finally, introducing alanine at five residues in Pocket 3, between the fingers and palm domains, inactivated PLpro: S212, Y213, Y251, K254, and Y305. Pocket 1 has a higher druggability score than Pockets 2 and 3. MD simulations showed that interactions within and between domains play critical roles in PLpro activity and thermal stability. The essential residues in Pockets 1 and 2 participate in a combination of intra- and inter-domain interactions. By contrast, the essential residues in Pocket three predominantly participate in inter-domain interactions. The most promising targets for therapeutic development are Pockets one and 3, which have the highest druggability score and the largest number of essential residues, respectively. Non-competitive inhibitors targeting these pockets may be antiviral agents against COVID-19 and related coronaviruses.

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SARS-COV-2 Coronavirus Papain-like Protease PLpro as an Antiviral Target for Inhibitors of Active Site and Protein-Protein Interactions.

Project description:The papain-like protease PLpro of the SARS-CoV-2 coronavirus is a multifunctional enzyme that catalyzes the proteolytic processing of two viral polyproteins, pp1a and pp1ab. PLpro also cleaves peptide bonds between host cell proteins and ubiquitin (or ubiquitin-like proteins), which is associated with a violation of immune processes. Nine structures of the most effective inhibitors of the PLpro active center were prioritized according to the parameters of biochemical (IC 50) and cellular tests to assess the suppression of viral replication (EC 50) and cytotoxicity (CC 50). A literature search has shown that PLpro can interact with at least 60 potential protein partners in cells, 23 of which are targets for other viral proteins (human papillomavirus and Epstein-Barr virus). The analysis of protein-protein interactions showed that the proteins USP3, UBE2J1, RCHY1, and FAF2 involved in deubiquitinylation and ubiquitinylation processes contain the largest number of bonds with other proteins; the interaction of viral proteins with them can affect the architecture of the entire network of protein-protein interactions. Using the example of a spatial model of the PLpro/ubiquitin complex and a set of 154 naturally occurring compounds with known antiviral activity, 13 compounds (molecular masses in the range of 454-954 Da) were predicted as potential PLpro inhibitors. These compounds bind to the "hot" amino acid residues of the protease at the positions Gly163, Asp164, Arg166, Glu167, and Tyr264 involved in the interaction with ubiquitin. Thus, pharmacological effects on peripheral PLpro sites, which play important roles in binding protein substrates, may be an additional target-oriented antiviral strategy.

| S-EPMC9984130 | biostudies-literature

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

Project description: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.

| S-EPMC9878345 | biostudies-literature

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