Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease

Xu, Yuling; Chen, Ke; Pan, Juanli; Lei, Yingshou; Zhang, Danting; Fang, Lipei; Tang, Jessica; Chen, Xin; Ma, Yanhong; Zheng, Yi; Bao, Zhenmin; Zhou, Yaoqi; Zhan, Jian; Xü, Wei

doi:10.1016/j.ijbiomac.2021.07.184

Cited by 36 publications

(49 citation statements)

References 37 publications

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“…Such an observation might be due to the involvement of different amino acid residues of PLpro protein in various interaction formations [ 68 ]. Recetly, Y. Xu et al [ 69 ], performed a high-throughput drug screening targeting SARS-CoV-2 PLpro resulting in the identification of Tanshinone IIA sulfonate sodium and chloroxine as the potential inhibitors of SARS-CoV-2 PLpro exhibiting docking based binding affinities of −8.6 and −5.9 kcal/mol, respectively. In docking study, they discovered that Tanshinone IIA sulfonate sodium interacted through π-π stacking and cation-π interaction with residues Tyr268 and Arg166, respectviely.…”

Section: Resultsmentioning

confidence: 99%

“…On the other hand, another compound chloroxine, establishes a binding interaction with Arg65. However, a long range MD simulation study revealed persistent associations of important amino acid residues Tyr264, Tyr273, Tyr268, and Gln269 in various interaction formations [ 69 ]. The present study also establishes a similar kind of binding interaction mechanism for the majority of the identified dietary compounds as exhibited in docking and MD simulation studies.…”

Section: Resultsmentioning

confidence: 99%

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Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

Bhowmick

Saha

AlFaris

et al. 2022

Journal of Molecular Graphics and Modelling

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The current ongoing pandemic of COVID-19 urges immediate treatment measures for controlling the highly contagious SARS-CoV-2 infections. The papain-like protease (PLpro), which is released from nsp3, is presently being evaluated as a significant anti-viral drug target for COVID-19 therapy development. Particularly, PLpro is implicated in the cleavage of viral polyproteins and antagonizes the host innate immune response through its deubiquitinating and deISGylating actions, thus making it a high-profile antiviral therapeutic target. The present study reports a few specific food compounds that can bind tightly with the SARS-CoV-2 PLpro protein identified through extensive computational screening techniques. Precisely, extensive advanced computational approaches combining target-based virtual screening, particularly employing sub-structure based similarity search, molecular docking, molecular dynamics (MD) simulations, and MM-GBSA based binding free energy calculations have been employed for the identification of the most promising food compounds with substantial functional implications as SARS-CoV-2 PLpro protein inhibitors/modulators. Observations from the present research investigation also provide a deeper understanding of the binding modes of the proposed four food compounds with SARS-CoV-2 PLpro protein. In docking analyses, all compounds have established essential inter-molecular interaction profiles at the active site cavity of the SARS-CoV-2 PLpro protein. Similarly, the long-range 100 ns conventional MD simulation studies also provided an in-depth understanding of probable interactions and dynamic behaviour of the SARS-CoV-2 PLpro protein-food compound complexes. Binding free energies of all molecular systems revealed a strong interaction affinity of food compounds towards the SARS-CoV-2 PLpro protein. Moreover, clear-cut comparative analyses against the known standard inhibitor also suggest that proposed food compounds may act as potential active chemical entities for modulating the action of the SARS-CoV-2 PLpro protein.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

Bhowmick

Saha

AlFaris

et al. 2022

Journal of Molecular Graphics and Modelling

View full text Add to dashboard Cite

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“…Compared with other coronaviral proteins, PLpro contributes to both virus replication and host cell signaling-cascade regulation, which is more suitable to be a target for antiviral drug design ( Baez-Santos et al, 2015 ). Using protease activity-based and high-throughput screening methods, two valuable SCoV2-PLpro inhibitors, tanshinone IIA sulfonate sodium, and chloroxine, are selected and show their potential in clinical treatment for COVID-19 ( Xu Y. et al, 2021 ). Ma et al (2021) identify Jun9-72-2 and Jun9-75-4 as the representatives of several SCoV2-PLpro inhibitors, with higher affinity than previously reported inhibitor GRL0617.…”

Section: Severe Acute Respiratory Syndrome Coronavirus-2 Infection and Cyclic Gmp-amp Synthase-stimulator Of Interferon Genesmentioning

confidence: 99%

“…Recently, multiple anticancer drugs have been repurposed of their capabilities in antiviral treatments ( Aldea et al, 2021 ; Xu Y. et al, 2021 ). For instance, β-arrestin 2 is a regulator of G protein-coupled receptor (GPCR) signaling pathways, promoting cGAMP production to regulate the cGAS-STING axis by targeting cGAS positively.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

et al. 2021

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Virus infection has been consistently threatening public health. The cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway is a critical defender to sense various pathogens and trigger innate immunity of mammalian cells. cGAS recognizes the pathogenic DNA in the cytosol and then synthesizes 2′3′-cyclic GMP-AMP (2′3′cGAMP). As the second messenger, cGAMP activates STING and induces the following cascade to produce type I interferon (IFN-I) to protect against infections. However, viruses have evolved numerous strategies to hinder the cGAS-STING signal transduction, promoting their immune evasion. Here we outline the current status of the viral evasion mechanism underlying the regulation of the cGAS-STING pathway, focusing on how post-transcriptional modifications, viral proteins, and non-coding RNAs involve innate immunity during viral infection, attempting to inspire new targets discovery and uncover potential clinical antiviral treatments.

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“… 14 , 29 − 31 Several compounds were identified as potential inhibitors of PLpro such as VIR250, VIR251, tanshinone IIA sulfonate sodium, and chloroxine. 17 , 31 In addition, noncovalent small-molecule SARS PLpro inhibitor GRL0617 is highly effective in reducing the activity of SARS-2 PLpro and showed high potency and excellent antiviral activity in a SARS-CoV-2 infection model. 16 , 18 Although GRL-0617 demonstrated good potency, there is a lack of data on its pharmacokinetic profile.…”

Section: Introductionmentioning

confidence: 99%

Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

et al. 2022

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Coronavirus disease 2019 (COVID-19) pandemic, a global health threat, was caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The SARS-CoV-2 papain-like cysteine protease (PLpro) was recognized as a promising drug target because of multiple functions in virus maturation and antiviral immune responses. Inhibitor GRL0617 occupied the interferon-stimulated gene 15 (ISG15) C-terminus-binding pocket and showed an effective antiviral inhibition. Here, we described a novel peptide–drug conjugate (PDC), in which GRL0617 was linked to a sulfonium-tethered peptide derived from PLpro-specific substrate LRGG. The EM-C and EC-M PDCs showed a promising in vitro IC50 of 7.40 ± 0.37 and 8.63 ± 0.55 μM, respectively. EC-M could covalently label PLpro active site C111 and display anti-ISGylation activities in cellular assays. The results represent the first attempt to design PDCs composed of stabilized peptide inhibitors and GRL0617 to inhibit PLpro. These novel PDCs provide promising opportunities for antiviral drug design.

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Repurposing clinically approved drugs for COVID-19 treatment targeting SARS-CoV-2 papain-like protease

Cited by 36 publications

References 37 publications

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

Identification of potent food constituents as SARS-CoV-2 papain-like protease modulators through advanced pharmacoinformatics approaches

The Regulatory Network of Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes Pathway in Viral Evasion

Design and Evaluation of a Novel Peptide–Drug Conjugate Covalently Targeting SARS-CoV-2 Papain-like Protease

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