SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses

Li, Fengling; Ghiabi, Pegah; Klíma, Martin; Li, Alice Shi Ming; Yazdi, Aliakbar Khalili; Chau, Irene; Loppnau, P.; Kutera, Maria; Seitova, Almagul; Bolotokova, Albina; Hutchinson, A.; Perveen, Sumera; Bouřa, Evžen; Vedadi, Masoud

doi:10.1016/j.bbagen.2023.130319

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…In fact, only a handful of inhibitors of viral MTases, mostly targeting flaviviruses 26,27 , were known prior to the COVID-19 pandemic. However, recently many inhibitors of SARS-CoV-2 MTases were reported by us and others 19,[28][29][30][31][32][33] .…”

Section: Discussionmentioning

confidence: 99%

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

et al. 2023

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Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2′-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2′-O-RNA MTase with enzymes from unrelated single-stranded RNA viruses (SARS-CoV-2 and Zika) reveals a conserved sinefungin binding mode, implicating that a single inhibitor could be used against unrelated viral families. Indeed, several of our inhibitors such as TO507 also inhibit the coronaviral nsp14 MTase.

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Section: Discussionmentioning

confidence: 99%

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

et al. 2023

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“…The active site of nsp14 is highly conserved among coronaviruses, and the compounds described here are highly likely to inhibit also nsp14 from SARS-CoV, MERS-CoV, or OC43 as recently shown with previous inhibitors by us and other groups. 26,44 Molecular docking studies of SARS-CoV-2 N7-MTase nsp14 in complex with one of the best inhibitor 7…”

Section: Rsc Medicinal Chemistrymentioning

confidence: 99%

N-Arylsulfonamide-based adenosine analogues to target RNA cap N7-methyltransferase nsp14 of SARS-CoV-2

Ahmed-Belkacem,

Troussier,

Delpal

et al. 2024

RSC Med. Chem.

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“…Such a trend of Nsp14−Nsp16 conservation has been shown for a much larger number of coronaviruses. 29 This may indicate that viruses with inactivating Nsp14−Nsp16 mutations may have less chance of having an efficient replication and survival. Therefore, targeting these methyltransferases could lead to development of pan-coronavirus therapeutics, a novel path perhaps in development of antivirals.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Similarly, SARS-CoV-2 Nsp14 shows 53, 55, 62, 61, 63, and 96% sequence identity to its orthologs in 299E, NL63, OC43, HKU1, MERS-CoV, and SARS-CoV-1. Such a trend of Nsp14–Nsp16 conservation has been shown for a much larger number of coronaviruses . This may indicate that viruses with inactivating Nsp14–Nsp16 mutations may have less chance of having an efficient replication and survival.…”

Section: Introductionmentioning

confidence: 99%

Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase

Singh

Fink

et al. 2023

J. Med. Chem.

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An under-explored target for SARS-CoV-2 is the S-adenosyl methionine (SAM)-dependent methyltransferase Nsp14, which methylates the N7-guanosine of viral RNA at the 5′-end, allowing the virus to evade host immune response. We sought new Nsp14 inhibitors with three large library docking strategies. First, up to 1.1 billion lead-like molecules were docked against the enzyme’s SAM site, leading to three inhibitors with IC50 values from 6 to 50 μM. Second, docking a library of 16 million fragments revealed 9 new inhibitors with IC50 values from 12 to 341 μM. Third, docking a library of 25 million electrophiles to covalently modify Cys387 revealed 7 inhibitors with IC50 values from 3.5 to 39 μM. Overall, 32 inhibitors encompassing 11 chemotypes had IC50 values < 50 μM and 5 inhibitors in 4 chemotypes had IC50 values < 10 μM. These molecules are among the first non-SAM-like inhibitors of Nsp14, providing starting points for future optimization.

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SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses

Cited by 12 publications

References 44 publications

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase

N-Arylsulfonamide-based adenosine analogues to target RNA cap N7-methyltransferase nsp14 of SARS-CoV-2

Structure-Based Discovery of Inhibitors of the SARS-CoV-2 Nsp14 N7-Methyltransferase

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