Author: Lichtman, Amos ; Mak, Lily ; Humeniuk, Rita ; Shaik, Naveed A. ; Xiao, Deqing ; Davies, Santosh ; Yue, Qin ; Castellanos, Keelin ; Peng, Chi‐Chi ; Abdelghany, Mazin ; Shen, Gong ; Winter, Helen ; Subramanian, Raju ; Anoshchenko, Olena ; Llewellyn, Joe ; Caro, Luzelena ; Hyland, Robert H. ; Duan, Ran ; Chen, Henry

There is an unmet need for safe and efficacious oral therapies for COVID‐19 with low potential for drug–drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS‐CoV‐2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS‐443902), which acts as an inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first‐in‐human, randomized, placebo‐controlled, phase I study following oral administration of obeldesivir and a phase I, open‐label absorption, distribution, metabolism, and excretion study following oral administration of [14C]‐obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT‐concentration analysis. The exposures to GS‐441524 increased dose proportionally in the 100–900‐mg dose range. GS‐441524 accumulated by 35% after twice‐daily and 12% after once‐daily dosing for 5 days. Dose‐proportional increases in the intracellular concentration of GS‐443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS‐441524 was not significantly altered by food intake. Following oral administration of [14C]‐obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]‐dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS‐441524 was the predominant plasma component (90% of 14C‐area under the concentration–time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice‐daily dosing regimen for further evaluation in phase III studies for COVID‐19.

08 Aug 2024·Journal of Medicinal Chemistry

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

Article

Author: Stray, Kirsten ; Vijjapurapu, Arya ; Ishida, Kazuya ; Perron, Michel ; Seung, Minji ; Tomkinson, Adrian ; Wang, Ting ; Kuehl, Philip J ; Feng, Joy Y ; Subramanian, Raju ; Doerffler, Edward ; Bilello, John P ; Marchand, Bruno ; Zhang, Lijun ; Xu, Yili ; Ellis, Scott ; Cihlar, Tomas ; Barauskas, Ona ; Clarke, Michael O ; Hui, Hon C ; Pitts, Jared ; Keeney, Michael ; Nayak, Arabinda ; Rautiola, Davin ; Murakami, Eisuke ; Kadrichu, Nani ; Yang, Hai ; Chun, Kwon ; Mackman, Richard L ; Chin, Gregory ; Riola, Nicholas C ; Siegel, Dustin S ; Palmiotti, Chris ; Ma, Bin ; Lee, Gary ; Perry, Jason K ; Irshad, Hammad ; Vermillion, Meghan S ; Goyal, Bindu ; Zhao, Xiaofeng

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 (EC₅₀ = 3-46 nM), human metapneumovirus (EC₅₀ = 210 nM), human rhinovirus (EC₅₀ = 54-61 nM), and enterovirus (EC₅₀ = 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.

01 Aug 2024·Journal of Biological Chemistry

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

Article

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

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.

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Indication	Highest Phase	Country/Location	Organization	Date
Coronavirus Infections	Preclinical	China	Sun Yat-Sen University	16 May 2022

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