Can Papain-like Protease Inhibitors Halt SARS-CoV-2 Replication?

Maiti, Biplab K.

doi:10.1021/acsptsci.0c00093

Cited by 40 publications

(34 citation statements)

References 18 publications

(30 reference statements)

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“…This is generally tackled using a strategy of translation from SARS-CoV to SARS-CoV-2 [ 164 ]. Antiviral activity and co-crystallized structures (PDB IDs: 6WUU and 6WX4) of PLpro peptide inhibitors are reported as well as zinc-containing advanced compounds for repurposing [ 165 ]. Recently, a series of high-quality co-crystals of SARS-CoV-2 PLpro with naphthyl ligands (PDB IDs: 7JN2, 7JNV, 7JIW, 7JIT and 7JIR) was made available by the Center for Structural Genomics of Infectious Diseases, which will help the structure-based design of novel inhibitors ( https://csgid.org/deposits/index/title_form:SARS ).…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

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Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

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“…Interestingly, the PL pro of SARS-CoV-1 preferentially cleaves ubiquitin over ISG15 [ 60 ]. The catalytic site of PL pro harbours the catalytic triad ( Figure 1 ): Cys-111, His-272, and Asp-286 [ 50 , 61 ]. The known non-covalent inhibitor GRL-0617 does not directly form contacts with the catalytic triad, but instead, it binds to a cavity nearby and induces the closure of blocking loop 2 (BL2) [ 53 , 62 ].…”

Section: Introductionmentioning

confidence: 99%

“…The zinc-binding site is coordinated by the conserved cysteines, Cys-189, Cys-192, Cys-224, and Cys-226. Zinc binding plays a significant role in the structural integrity of the protein [ 50 , 61 ].…”

Section: Introductionmentioning

confidence: 99%

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

2021

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The ongoing coronavirus pandemic has been a burden on the worldwide population, with mass fatalities and devastating socioeconomic consequences. It has particularly drawn attention to the lack of approved small-molecule drugs to inhibit SARS coronaviruses. Importantly, lessons learned from the SARS outbreak of 2002-2004, caused by severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1), can be applied to current drug discovery ventures. SARS-CoV-1 and SARS-CoV-2 both possess two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), which play a significant role in facilitating viral replication, and are important drug targets. The non-covalent inhibitor, GRL-0617, which was found to inhibit replication of SARS-CoV-1, and more recently SARS-CoV-2, is the only PLpro inhibitor co-crystallised with the recently solved SARS-CoV-2 PLpro crystal structure. Therefore, the GRL-0617 structural template and pharmacophore features are instrumental in the design and development of more potent PLpro inhibitors. In this work, we conducted scaffold hopping using GRL-0617 as a reference to screen over 339,000 ligands in the chemical space using the ChemDiv, MayBridge, and Enamine screening libraries. Twenty-four distinct scaffolds with structural and electrostatic similarity to GRL-0617 were obtained. These proceeded to molecular docking against PLpro using the AutoDock tools. Of two compounds that showed the most favourable predicted binding affinities to the target site, as well as comparable protein-ligand interactions to GRL-0617, one was chosen for further analogue-based work. Twenty-seven analogues of this compound were further docked against the PLpro, which resulted in two additional hits with promising docking profiles. Our in silico pipeline consisted of an integrative four-step approach: (1) ligand-based virtual screening (scaffold-hopping), (2) molecular docking, (3) an analogue search, and, (4) evaluation of scaffold drug-likeness, to identify promising scaffolds and eliminate those with undesirable properties. Overall, we present four novel, and lipophilic, scaffolds obtained from an exhaustive search of diverse and uncharted regions of chemical space, which may be further explored in vitro through structure-activity relationship (SAR) studies in the search for more potent inhibitors. Furthermore, these scaffolds were predicted to have fewer off-target interactions than GRL-0617. Lastly, to our knowledge, this work contains the largest ligand-based virtual screen performed against GRL-0617.

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“…A shortcut approach is to repurpose widely available, inexpensive drugs that can be easily administered against SARS-CoV-2. Most studies target a single SARS-CoV-2 protein 3 such as the spike protein that mediates cell entry, 4 the main protease (M pro ) 5,6 or the papain-like protease (PL pro ) 7 that cleaves the viral polyprotein into its constituent proteins, or the RNA-dependent RNA polymerase (RdRp) that catalyzes viral RNA synthesis. 8,9 However, the virus may evade anti-viral drugs that target a single viral protein since the spike receptor-binding domain is the most variable, 10 whereas human proteases may substitute for viral proteases.…”

Section: Introductionmentioning

confidence: 99%

Synergistic Inhibition of SARS-CoV-2 Replication using Disulfiram/Ebselen and Remdesivir

Chen¹,

Fei²,

Sargsyan

et al. 2021

Preprint

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The SARS-CoV-2 replication and transcription complex (RTC) comprising nonstructural protein (nsp) 2-16 plays crucial roles in viral replication, reducing the efficacy of broad-spectrum nucleoside analog drugs such as remdesivir and in evading innate immune responses. Most studies target a specific viral component of the RTC such as the main protease or the RNA-dependent RNA polymerase. In contrast, our strategy is to target multiple conserved domains of the RTC to prevent SARS-CoV-2 genome replication and to create a high barrier to viral resistance or evasion of antiviral drugs. We show that clinically-safe Zn-ejector drugs, disulfiram/ebselen, can target conserved Zn2+-sites in SARS-CoV-2 nsp13 and nsp14 and inhibit nsp13 ATPase and nsp14 exoribonuclease activities. As the SARS-CoV-2 nsp14 domain targeted by disulfiram/ebselen is involved in RNA fidelity control, our strategy allows coupling of the Zn-ejector drug with a broad-spectrum nucleoside analog that would otherwise be excised by the nsp14 proofreading domain. As proof-of-concept, we show that disulfiram, when combined with remdesivir, can synergistically inhibit SARS-CoV-2 replication in Vero E6 cells. We present a mechanism of action and the advantages of our multi-targeting strategy, which can be applied to any type of coronavirus with conserved Zn2+-sites.

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Can Papain-like Protease Inhibitors Halt SARS-CoV-2 Replication?

Cited by 40 publications

References 18 publications

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Establishing an Analogue Based In Silico Pipeline in the Pursuit of Novel Inhibitory Scaffolds against the SARS Coronavirus 2 Papain-Like Protease

Synergistic Inhibition of SARS-CoV-2 Replication using Disulfiram/Ebselen and Remdesivir

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