ArticleAntimicrobial agents and chemotherapy2008
Design and profiling of GS-9148, a novel nucleotide analog active against nucleoside-resistant variants of human immunodeficiency virus type 1, and its orally bioavailable phosphonoamidate prodrug, GS-9131.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 94 citations in OpenAlex.
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- 2'-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects.National science review · 2024Review
- Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.Antimicrobial agents and chemotherapy · 2024Article
- Prodrugs of a 1-Hydroxy-2-oxopiperidin-3-yl Phosphonate Enolase Inhibitor for the Treatment ofJournal of medicinal chemistry · 2022Article
- Long-acting HIV pre-exposure prophylaxis (PrEP) approaches: recent advances, emerging technologies, and development challenges.Expert opinion on drug delivery · 2022Review
- An Update on Antiretroviral Therapy.Advances in experimental medicine and biology · 2021Article
- Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery.The Journal of biological chemistry · 2020Review
- Overview of Biologically Active Nucleoside Phosphonates.Frontiers in chemistry · 2020Review
- Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases.Future medicinal chemistry · 2019Review
- Emerging reverse transcriptase inhibitors for HIV-1 infection.Expert opinion on emerging drugs · 2018Review
- Highly convergent synthesis and antiviral activity of (E)-but-2-enyl nucleoside phosphonoamidates.European journal of medicinal chemistry · 2018Article
- Long-Acting HIV Treatment and Prevention: Closer to the Threshold.Global health, science and practice · 2017Article
- Antiviral Activity of Bictegravir (GS-9883), a Novel Potent HIV-1 Integrase Strand Transfer Inhibitor with an Improved Resistance Profile.Antimicrobial agents and chemotherapy · 2016Article
- Intracellular Activation of Tenofovir Alafenamide and the Effect of Viral and Host Protease Inhibitors.Antimicrobial agents and chemotherapy · 2016Article
- In Vitro Virology Profile of Tenofovir Alafenamide, a Novel Oral Prodrug of Tenofovir with Improved Antiviral Activity Compared to That of Tenofovir Disoproxil Fumarate.Antimicrobial agents and chemotherapy · 2015Article
- Adenine: an important drug scaffold for the design of antiviral agents.Acta pharmaceutica Sinica. B · 2015Review
- Tenofovir-induced nephrotoxicity: incidence, mechanism, risk factors, prognosis and proposed agents for prevention.European journal of clinical pharmacology · 2014Review
- Tenofovir diphosphate concentrations and prophylactic effect in a macaque model of rectal simian HIV transmission.The Journal of antimicrobial chemotherapy · 2014Article
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18 authors at 1 institution in 1 country.
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Abstract
GS-9148 [(5-(6-amino-purin-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is a novel ribose-modified human immunodeficiency virus type 1 (HIV-1) nucleotide reverse transcriptase (RT) inhibitor (NRTI) selected from a series of nucleoside phosphonate analogs for its favorable in vitro biological properties including (i) a low potential for mitochondrial toxicity, (ii) a minimal cytotoxicity in renal proximal tubule cells and other cell types, (iii) synergy in combination with other antiretrovirals, and (iv) a unique resistance profile against multiple NRTI-resistant HIV-1 strains. Notably, antiviral resistance analysis indicated that neither the K65R, L74V, or M184V RT mutation nor their combinations had any effect on the antiretroviral activity of GS-9148. Viruses carrying four or more thymidine analog mutations showed a substantially smaller change in GS-9148 activity relative to that observed with most marketed NRTIs. GS-9131, an ethylalaninyl phosphonoamidate prodrug designed to maximize the intracellular delivery of GS-9148, is a potent inhibitor of multiple subtypes of HIV-1 clinical isolates, with a mean 50% effective concentration of 37 nM. Inside cells, GS-9131 is readily hydrolyzed to GS-9148, which is further phosphorylated to its active diphosphate metabolite (A. S. Ray, J. E. Vela, C. G. Boojamra, L. Zhang, H. Hui, C. Callebaut, K. Stray, K.-Y. Lin, Y. Gao, R. L. Mackman, and T. Cihlar, Antimicrob. Agents Chemother. 52:648-654, 2008). GS-9148 diphosphate acts as a competitive inhibitor of RT with respect to dATP (K(i) = 0.8 muM) and exhibits low inhibitory potency against host polymerases including DNA polymerase gamma. Oral administration of GS-9131 to beagle dogs at a dose of 3 mg/kg of body weight resulted in high and persistent levels of GS-9148 diphosphate in peripheral blood mononuclear cells (with a maximum intracellular concentration of >9 microM and a half-life of >24 h). This favorable preclinical profile makes GS-9131 an attractive clinical development candidate for the treatment of patients infected with NRTI-resistant HIV.
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