Mechanism and spectrum of inhibition of a 4′-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses

Gordon, Calvin J.; Walker, Simon M.; Tchesnokov, Egor P.; Kocincova, Dana; Pitts, Jared; Siegel, Dustin S.; Perry, Jason K.; Feng, Joy Y.; Bilello, John P.; Götte, Matthias

doi:10.1016/j.jbc.2024.107514

Cited by 1 publication

(2 citation statements)

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“…The 4′-CN of 2-NTP occupies a pocket formed by palm residues F704, N705, Q782, W785, T786, and G810. Further structural analysis of 2-NTP is included in a broader mechanism of action study by Gordon et al The model, together with the 2-NTP data reported in Table , supports the proposed mechanism of selective Pol binding followed by the incorporation of 2-NTP into viral RNA.…”

Section: Resultsmentioning

confidence: 65%

“…1 was inactive against influenza A (FluA, at 2 μM) and had low potency against severe acute respiratory coronavirus-2 (SARS-CoV-2; EC 50 = 4.75 ± 1.35 μM). Further mechanistic discussion is included in a broader mechanism of action study by Gordon et al Importantly, 1 demonstrated broad-spectrum potent activity against pneumo- and picornaviruses commonly associated with disease exacerbation for people with asthma or COPD.…”

Section: Resultsmentioning

confidence: 99%

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Discovery of GS-7682, a Novel 4′-Cyano-Modified C-Nucleoside Prodrug with Broad Activity against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys

Siegel,

Hui,

Pitts

et al. 2024

J. Med. Chem.

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Acute respiratory viral infections, such as pneumovirus and respiratory picornavirus infections, exacerbate disease in COPD and asthma patients. A research program targeting respiratory syncytial virus (RSV) led to the discovery of GS-7682 (1), a novel phosphoramidate prodrug of a 4′-CN-4-aza-7,9-dideazaadenosine C-nucleoside GS-646089 (2) with broad antiviral activity against RSV (EC 50 = 3−46 nM), human metapneumovirus (EC 50 = 210 nM), human rhinovirus (EC 50 = 54−61 nM), and enterovirus (EC 50 = 83−90 nM). Prodrug optimization for cellular potency and lung cell metabolism identified 5′-methyl [(S)hydroxy(phenoxy)phosphoryl]-L-alaninate in combination with 2′,3′-diisobutyrate promoieties as being optimal for high levels of intracellular triphosphate formation in vitro and in vivo. 1 demonstrated significant reductions of viral loads in the lower respiratory tract of RSV-infected African green monkeys when administered once daily via intratracheal nebulized aerosol. Together, these findings support additional evaluation of 1 and its analogues as potential therapeutics for pneumo-and picornaviruses.

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 99%