Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3

Virdi, Rajdeep S; Bavisotto, Robert; Hopper, Nicholas C; Vuksanovic, Nemanja; Melkonian, Trevor R; Silvaggi, N.R.; Frick, David N.

doi:10.1177/2472555220960428

Cited by 38 publications

(39 citation statements)

References 26 publications

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“…This screening confirms previous reports demonstrating anti-SARS-CoV-2 activity of hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, celecoxib, and thioridazine hydrochloride (8)(9)(10)(25)(26)(27), while identifying additional 12 drugs. However, there are seven drugs have been reported when our manuscript was underreview (28)(29)(30)(31)(32)(33)(34)(35)(36)(37). The underlying mechanisms of viral replication inhibition by these drugs are not clear.…”

Section: Discussionmentioning

confidence: 94%

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

et al. 2020

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COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

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Section: Discussionmentioning

confidence: 94%

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

et al. 2020

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“…S1) and functional perspective of the SARS-CoV-2 protein mutations reported here provide some useful information for the therapeutics. The PL-pro domain and macrodomain of Nsp3 can be potential drug targets as they are less prone to mutations ( Virdi et al, 2020 ). Occurrence of S25L mutation in Nsp7, which is in the proximity to Nsp7-Nsp8 binding interface and the proximity of Nsp12:P323L to the Nsp12-Nsp8 binding site indicate their possible role in modulating the viral replication mechanism.…”

Section: Discussionmentioning

confidence: 99%

Global variation in SARS-CoV-2 proteome and its implication in pre-lockdown emergence and dissemination of 5 dominant SARS-CoV-2 clades

Patro

Sathyaseelan

Uttamrao

et al. 2021

Infection, Genetics and Evolution

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SARS-CoV-2 is currently causing major havoc worldwide with its efficient transmission and propagation. To track the emergence as well as the persistence of mutations during the early stage of the pandemic, a comparative analysis of SARS-CoV-2 whole proteome sequences has been performed by considering manually curated 31,389 whole genome sequences from 84 countries. Among the 7 highly recurring (percentage frequency≥10%) mutations (Nsp2:T85I, Nsp6:L37F, Nsp12:P323L, Spike:D614G, ORF3a:Q57H, N protein:R203K and N protein:G204R), N protein:R203K and N protein: G204R are co-occurring (dependent) mutations. Nsp12:P323L and Spike:D614G often appear simultaneously. The highly recurring Spike:D614G, Nsp12:P323L and Nsp6:L37F as well as moderately recurring (percentage frequency between ≥1 and <10%) ORF3a:G251V and ORF8:L84S mutations have led to4 major clades in addition to a clade that lacks high recurring mutations. Further, the occurrence of ORF3a:Q57H&Nsp2:T85I, ORF3a:Q57H and N protein:R203K&G204R along with Nsp12:P323L&Spike:D614G has led to 3 additional sub-clades. Similarly, occurrence of Nsp6:L37F and ORF3a:G251V together has led to the emergence of a sub-clade. Nonetheless, ORF8:L84S does not occur along with ORF3a:G251V or Nsp6:L37F. Intriguingly, ORF3a:G251V and ORF8:L84S are found to occur independent of Nsp12:P323L and Spike:D614G mutations. These clades have evolved during the early stage of the pandemic and have disseminated across several countries. Further, Nsp10 is found to be highly resistant to mutations, thus, it can be exploited for drug/vaccine development and the corresponding gene sequence can be used for the diagnosis. Concisely, the study reports the SARS-CoV-2 antigens diversity across the globe during the early stage of the pandemic and facilitates the understanding of viral evolution.

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“…In light of the current situation regarding the COVID-19 pandemic, we chose to demonstrate the applicability of this binding system for screening of small molecule inhibitors against the macrodomain of SARS-CoV-2 nsp3. Presently, efforts are being made by researchers worldwide to find inhibitors against this macrodomain (Bonfiglio et al, 2020;Brosey et al, 2021;Cantini et al, 2020;Michalska et al, 2020;Ni et al, 2021;Russo et al, 2021;Schuller et al, 2021;Virdi et al, 2020). The nsp3 macrodomain of coronaviruses was shown to be critical for the viral replication (Fehr et al, 2015(Fehr et al, , 2016, and therefore small molecule inhibitors might show promise as therapeutic agents to fight infections caused by SARS-CoV-2 (COVID-19) and other viruses.…”

Section: Application Example: Screening For Inhibitors Against the Sars-cov-2 Nsp3 Macrodomainmentioning

confidence: 99%

A molecular toolbox for ADP-ribosyl binding proteins

Sowa

Galera‐Prat

Wazir

et al. 2021

Preprint

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Proteins interacting with ADP-ribosyl groups are often involved in disease-related pathways or in viral infections, which makes them attractive targets for the development of inhibitors. Our goal was to develop a robust and accessible assay technology that is suitable for high-throughput screening and applicable to a wide range of proteins acting as either hydrolysing or non-hydrolysing binders of mono- and poly-ADP-ribosyl groups. As a foundation of our work, we developed a C-terminal protein fusion tag based on a Gi protein alpha subunit peptide (GAP), which allows for site-specific introduction of cysteine-linked mono- and poly-ADP-ribosyl groups as well as chemical ADP-ribosyl analogs. By fusion of the GAP-tag and ADP-ribosyl binders to fluorescent proteins, we were able to generate robust FRET signals and the interaction with 22 previously described ADP-ribosyl-binders was confirmed. To demonstrate the applicability of this binding assay for high-throughput screening, we utilized it to screen for inhibitors of the SARS-CoV-2 nsp3 macrodomain and identified the drug suramin as a moderate yet unspecific inhibitor of this protein. To complement the binding technology, we prepared high-affinity ADP-ribosyl binders fused to a nanoluciferase, which enabled simple blot-based detection of mono- and poly-ADP-ribosylated proteins. These tools can be expressed recombinantly in E. coli using commonly available agents and will help to investigate ADP-ribosylation systems and aid in drug discovery.

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Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3

Cited by 38 publications

References 26 publications

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2

Global variation in SARS-CoV-2 proteome and its implication in pre-lockdown emergence and dissemination of 5 dominant SARS-CoV-2 clades

A molecular toolbox for ADP-ribosyl binding proteins

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