Known Inhibitors of SARS-CoV-2 Nsp-13 (helicase) - Google Doc

[TomkUCL]

A table of known nsp13 inhibitors in the literature can be found here. Users are encouraged to add known inhibitors that are not already in the table following the format shown:

The google doc can be found here: https://docs.google.com/document/d/1aDMDrQo6alDvjMkXfTjfuPcpdEAvAt1oNj8EB6CgXtc/edit?usp=sharing

[ahsgc]

Working sheet on viral helicase inhibitors:

https://docs.google.com/spreadsheets/d/11GLXrOoXxF5Vpi3Ej0tTF-IjmdgQCU7L/edit?usp=sharing&ouid=105040681564408325839&rtpof=true&sd=true

[mattodd]

OK, so we need to coalesce into one document/sheet, and we need to make sure we're collating the necessary info. DOIs for sure, and the year of publication (so we can sort if we want). Are we here identifying inhibitors of Nsp13 or are we doing viral helicases? What's our scope at this stage @ahsgc @TomkUCL ?

Ping @tmw20653 and will try to get Peter Brown on here.

[ahsgc]

@mattodd In this excel sheet, I added helicase inhibitors to find out any potential templates. I will narrow it down to NSP13 ASAP.

My suggestion is to use an excel file instead of google word (for flexibility and sorting). I can merge these two documents @TomkUCL.

[mattodd]

Pasting here in case we don't already have this: https://pubs.acs.org/doi/10.1021/acs.jpclett.0c02421 Discovery of COVID-19 Inhibitors Targeting the SARS-CoV-2 Nsp13 Helicase, Mark Andrew White, Wei Lin, and Xiaodong Cheng J. Phys. Chem. Lett. 2020, 11, 21,

[mattodd]

@SumeraMalik123 wrote in a recent meeting: A serial of potential drugs, including flavonoids, myricetin, scultellarein, dihydroxychromones, aryl diketoacids, 3-[(2-nitrophenyl)sulphanylmethyl]- 4prop-2-enyl-1H-1,2,4-triazole-5-thione and bismuth salts had been found by different groups to target the ATPase/ helicase activities of SARS-CoV nsp13 (Seybert et al. 2005; Yang et al. 2007a, b; Lee et al. 2009; Adedeji et al. 2012; Yu et al. 2012). Note - not SARS2 If these refs are incorporated either in wiki or in paper, this comment can be hidden, with a note to that effect.

[ahsgc]

These compounds are already listed in our common excel file with relevant citations.

I will cross-check once again.

@SumeraMalik123 Thank you for sharing these.

[SumeraMalik123]

Here are a few more licoflavone C, a novel small compound (7-ethyl-8-mercapto-3-methyl-3,7-dihydro-1H-purine-2,6-dione also designed as EMMDPD), guanidine hydrochloride (GuHCl), ebselen, Bismuth potassium citrate, Ranitidine bismuth citrate, Bismuth citrate, three small organic molecules (bananin, SSYA10-00, and chromone-4c), other small molecules (ChemDive ID: F306-0053 and 5645-0263), suramin-like compounds and FPA-124. G-Quadruplexes (G4s) ligands may exert a reasonably antiviral activity as well

[TomkUCL]

Published October 2022: Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro https://www.sciencedirect.com/science/article/pii/S0166354222001589?via%3Dihub SPR was used for screening.

Quote "a structural comparison between the APO (PDB ID: 7NIO) and AMP-PNP-bound (PDB ID: 7NNO) NSP13 revealed marked conformational changes in PUG-binding site and nucleic substrate-binding motifs (Fig. 5E). Thus, we proposed that PUG binding might keep NSP13 in an open conformation (APO form, in blue color), and allosterically induces conformational changes in the nucleic acid binding region, thereby preventing DNA from binding. Collectively, these results thus suggest that PUG inhibits NSP13 through blocking the binding of both ATP and nucleic acid substrates" PUG was identified as an allosteric inhibitor of SARS-CoV-2 3CLpro main protease (Du et al., 2021; Khalifa et al., 2020; Tito et al., 2021), which functions to cleave the polyproteins to generate nonstructural proteins. Moreover, PUG was also shown to interfere with the interaction between the virus spike glycoprotein and the cellular receptor ACE2 (Surucic et al., 2021; Tito et al., 2021), and thereby might have potential inhibitory effects on the virus entry into the host cells. Our results showed that PUG directly binds NSP13 with a KD value of 21.6 nM, inhibits the helicase activity of NSP13 (IC50 ∼ 430 nM). However, because these PUG-targeting proteins play different roles in the different stages of virus life cycle, we conclude that the potent anti-SARS-CoV-2 efficacy of PUG in the cells may be attributed to the multi-targeting effect.

[ahsgc]

A summary of chemotypes for SARS-CoV-2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188765/

S107042802105002X.pdf

@TomkUCL @mattodd @tmw20653

[tmw20653]

Anwar,

There is a primary sulfonamide that they list as a SARS-CoV helicase inhibitor https://pubmed.ncbi.nlm.nih.gov/28910865/

Tim

From: Anwar Hossain @.> Date: Sunday, October 23, 2022 at 7:55 PM To: StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B @.> Cc: Willson, Tim @.>, Mention @.> Subject: Re: [StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B] Known Inhibitors of SARS-CoV-2 Nsp-13 (helicase) - Google Doc (Issue #22)

A summary of chemotypes for SARS-CoV-2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188765/

S107042802105002X.pdfhttps://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/files/9847843/S107042802105002X.pdf

@TomkUCLhttps://github.com/TomkUCL @mattoddhttps://github.com/mattodd @tmw20653https://github.com/tmw20653

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[ahsgc]

@tmw20653

I found several other similar molecules active against NSP13. I am now working on designing a small library (from a similarity search) to purchase or synthesize (an addition to our current thiazole series).

From docking:

Ref: https://www.sciencedirect.com/science/article/pii/S1093326322000018?via%3Dihub

Thank you, Tim!

Anwar

[tmw20653]

Anwar,

I am skeptical of Raubenolt paper, since it contains only molecular docking and no experimental data on nsp13 inhibitionn.

Tim

From: Anwar Hossain @.> Date: Sunday, October 23, 2022 at 9:23 PM To: StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B @.> Cc: Willson, Tim @.>, Mention @.> Subject: Re: [StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B] Known Inhibitors of SARS-CoV-2 Nsp-13 (helicase) - Google Doc (Issue #22)

@tmw20653https://github.com/tmw20653

I found several other similar molecules active against NSP13. I am now working on designing a small library (from a similarity search) to purchase or synthesize (an addition to our current thiazole series).

From docking:

[image]https://user-images.githubusercontent.com/108078845/197429654-a47029bb-797b-4307-ab87-b1a91c0114b8.png

Ref: https://www.sciencedirect.com/science/article/pii/S1093326322000018?via%3Dihub

Thank you, Tim!

Anwar

— Reply to this email directly, view it on GitHubhttps://github.com/StructuralGenomicsConsortium/CNP4-Nsp13-C-terminus-B/issues/22#issuecomment-1288280013, or unsubscribehttps://github.com/notifications/unsubscribe-auth/AGJI3JB44BB3KWHE5VO7FRTWEXQIJANCNFSM52SPZ2QA. You are receiving this because you were mentioned.Message ID: @.***>

[ahsgc]

Agreed! I see it is commercially available without a biological profile. I will keep track of this molecule as optional!

Anwar