Biology subjects

Vijjapurapu, A.

Publications and source records attributed to Vijjapurapu, A..

2 recordsLinked to original sources

bioRxiv2025

Oral dosing of the nucleoside analog obeldesivir is efficacious against RSV infection in African green monkeys

Respiratory syncytial virus (RSV) is a significant cause of morbidity and mortality in high-risk populations. Although prophylactic options are available, there are no effective oral therapeutics for RSV infection. Obeldesivir (ODV) is an orally bioavailable prodrug of the nucleoside analog GS-441524, which is converted intracellularly to its active nucleoside triphosphate and inhibits the RSV RNA polymerase. Here we report the potent antiviral activity of ODV against geographically and temporally diverse RSV A and B clinical isolates (EC50: 0.20-0.66 M). Resistance selection studies with ODV and GS-441524 against RSV identified a single amino acid substitution, I777L, in the L polymerase with reduced susceptibility (3.3-3.8-fold) to ODV and GS-441524, indicating a high barrier for resistance development. In an African green monkey RSV infection model, once-daily oral ODV doses of 30 or 90 mg/kg initiated [~]24 hours post-infection significantly reduced log10 viral RNA copies/mLxday area under the curve by 69-92% in the upper and lower respiratory tracts. Together, these preclinical data support the clinical evaluation of ODV for the treatment of RSV infection.

microbiology↗

bioRxiv2024

Discovery and Synthesis of GS-7682, a Novel Prodrug of a 4'-CN-4-Aza-7,9-Dideazaadenosine C-Nucleoside with Broad-Spectrum Potency Against Pneumo- and Picornaviruses and Efficacy in RSV-Infected African Green Monkeys.

Acute respiratory viral infections (ARVI), 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 (hMPV) EC50 = 210 {+/-} 50 nM, human rhinovirus (RV) EC50 = 54-61 nM, and enterovirus (EV) EC50 = 83-90 nM. Prodrug optimization for cellular potency and lung cell metabolism identified the 5-methyl((S)-hydroxy(phenoxy)phosphoryl)-L-alaninate in combination with 2,3-diisobutyrate promoieties as optimal for high 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 finding support additional evaluation of 1 and its analogs as a potential therapeutic for pneumo- and picornaviruses.

biochemistry↗