This study explores the repurposing of Food and Drug Administration (FDA)-approved drugs as potential inhibitors of SARS-CoV-2 papain-like protease (PLpro), a critical enzyme for viral replication. Initially, 3009 FDA approved drugs were screened to identify candidates structurally similar to the co-crystallized ligand XT7 in the SARS-CoV-2 PLpro complex (PDB ID: 7LBR). A fingerprint analysis narrowed the selection to the top 5% )150 drugs) most structurally akin to XT7, followed by a more refined structural similarity test that identified the top 1% (30 drugs). Molecular docking studies highlighted several compounds with strong binding affinities to the SARS-CoV-2 PLpro. Notably, Fedratinib exhibited a particularly robust binding energy of [Formula: see text]kcal/mol and was chosen for further investigation. Subsequent molecular dynamics (MD) simulations over 100 ns confirmed the stability and efficacy of Fedratinib’s binding, as evidenced by favorable energetic and dynamic profiles. The molecular mechanics-generalized born surface area (MM-GBSA) calculations corroborated these findings, revealing a binding energy of [Formula: see text]kcal/mol. Additionally, PLIP, ProLIF, and PCAT analyses further validated the stability and interactions of the PLpro-Fedratinib complex observed during the MD simulations. Overall, our results indicate that Fedratinib, an FDA-approved drug, demonstrates promising potential as an inhibitor of SARS-CoV-2 PLpro, warranting further in vitro and in vivo experimental validation as well as potential clinical evaluation.

22 Aug 2024·Journal of Medicinal Chemistry

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

Article

Author: Shen, Zhengnan ; J Thatcher, Gregory R. ; Schenten, Dominik ; Ramos, Omar Lozano ; Fu, Jiqiang ; Velma, Ganga Reddy ; Xiong, Rui ; Musku, Soumya Reddy ; Cooper, Laura ; Li, Zuomei ; Soleymani, Farinaz ; Rong, Lijun ; Ratia, Kiira ; Indukuri, Divakar ; Rychetsky, Pavel ; Slilaty, Steve ; Holberg, Cameron

The SARS-CoV-2 papain-like protease (PLpro), essential for viral processing and immune response disruption, is a promising target for treating acute infection of SARS-CoV-2. To date, there have been no reports of PLpro inhibitors with both submicromolar potency and animal model efficacy. To address the challenge of PLpro's featureless active site, a noncovalent inhibitor library with over 50 new analogs was developed, targeting the PLpro active site by modulating the BL2-loop and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed pharmacokinetically. 10, in particular, showed a significant lung accumulation, up to 12.9-fold greater than plasma exposure, and was effective in a mouse model of SARS-CoV-2 infection, as well as against several SARS-CoV-2 variants. These findings highlight the potential of 10 as an in vivo chemical probe for studying PLpro inhibition in SARS-CoV-2 infection.

24 Feb 2022·Journal of Medicinal ChemistryQ1 · MEDICINE

Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity

Q1 · MEDICINE

Article

Author: Huang, Fei ; Thatcher, Gregory R. J. ; Lee, Hyun ; Kong, Deyu ; Rong, Lijun ; Ratia, Kiira ; Cooper, Laura ; Xiong, Rui ; Li, Yangfeng ; Alqarni, Saad ; Dubrovskyi, Oleksii ; Shen, Zhengnan ; Kwon, Youngjin

Antiviral agents that complement vaccination are urgently needed to end the COVID-19 pandemic. The SARS-CoV-2 papain-like protease (PLpro), one of only two essential cysteine proteases that regulate viral replication, also dysregulates host immune sensing by binding and deubiquitination of host protein substrates. PLpro is a promising therapeutic target, albeit challenging owing to featureless P1 and P2 sites recognizing glycine. To overcome this challenge, we leveraged the cooperativity of multiple shallow binding sites on the PLpro surface, yielding novel 2-phenylthiophenes with nanomolar inhibitory potency. New cocrystal structures confirmed that ligand binding induces new interactions with PLpro: by closing of the BL2 loop of PLpro forming a novel "BL2 groove" and by mimicking the binding interaction of ubiquitin with Glu167 of PLpro. Together, this binding cooperativity translates to the most potent PLpro inhibitors reported to date, with slow off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronavirus Infections	Preclinical	United States	University of Arizona	05 Aug 2024

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