ArticleAntimicrobial agents and chemotherapy2011
In vitro characterization of GS-8374, a novel phosphonate-containing inhibitor of HIV-1 protease with a favorable resistance profile.
Article in Antimicrobial agents and chemotherapy, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 34 citations in OpenAlex.
- Advancements in development of novel class of HIV protease inhibitors.Annals of medicine · 2026Review
- On-Resin Assembly of Macrocyclic Inhibitors ofJournal of medicinal chemistry · 2025Article
- Phenotypic Characterization of Replication-Impaired Lenacapavir-Resistant HIV Clinical Isolates.Journal of medical virology · 2025Article
- Development of Anti-HIV Therapeutics: From Conventional Drug Discovery to Cutting-Edge Technology.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Preclinical characterization of a non-peptidomimetic HIV protease inhibitor with improved metabolic stability.Antimicrobial agents and chemotherapy · 2024Article
- HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues.European journal of medicinal chemistry · 2023Article
- Re-emerging Aspartic Protease Targets: ExaminingJournal of medicinal chemistry · 2021Article
- Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond.Chemical reviews · 2021Review
- Inhibiting HTLV-1 Protease: A Viable Antiviral Target.ACS chemical biology · 2021Article
- Article
- Recent Progress in the Development of HIV-1 Protease Inhibitors for the Treatment of HIV/AIDS.Journal of medicinal chemistry · 2016Review
- 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
- GS-8374, a prototype phosphonate-containing inhibitor of HIV-1 protease, effectively inhibits protease mutants with amino acid insertions.Journal of virology · 2014Article
- P2' benzene carboxylic acid moiety is associated with decrease in cellular uptake: evaluation of novel nonpeptidic HIV-1 protease inhibitors containing P2 bis-tetrahydrofuran moiety.Antimicrobial agents and chemotherapy · 2013Article
- Mutations in multiple domains of Gag drive the emergence of in vitro resistance to the phosphonate-containing HIV-1 protease inhibitor GS-8374.Journal of virology · 2013Article
- Cobicistat boosts the intestinal absorption of transport substrates, including HIV protease inhibitors and GS-7340, in vitro.Antimicrobial agents and chemotherapy · 2012Article
- Enhancing protein backbone binding--a fruitful concept for combating drug-resistant HIV.Angewandte Chemie (International ed. in English) · 2012Review
- Protease-Mediated Maturation of HIV: Inhibitors of Protease and the Maturation Process.Molecular biology international · 2012Article
- GS-8374, a novel HIV protease inhibitor, does not alter glucose homeostasis in cultured adipocytes or in a healthy-rodent model system.Antimicrobial agents and chemotherapy · 2011Article
Corrections and comments
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Authors and funding
19 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GS-8374 is a novel bis-tetrahydrofuran HIV-1 protease (PR) inhibitor (PI) with a unique diethylphosphonate moiety. It was selected from a series of analogs containing various di(alkyl)phosphonate substitutions connected via a linker to the para position of a P-1 phenyl ring. GS-8374 inhibits HIV-1 PR with high potency (K(i) = 8.1 pM) and with no known effect on host proteases. Kinetic and thermodynamic analysis of GS-8374 binding to PR demonstrated an extremely slow off rate for the inhibitor and favorable contributions of both the enthalpic and entropic components to the total free binding energy. GS-8374 showed potent antiretroviral activity in T-cell lines, primary CD4(+) T cells (50% effective concentration [EC(50)] = 3.4 to 11.5 nM), and macrophages (EC(50) = 25.5 nM) and exhibited low cytotoxicity in multiple human cell types. The antiviral potency of GS-8374 was only moderately affected by human serum protein binding, and its combination with multiple approved antiretrovirals showed synergistic effects. When it was tested in a PhenoSense assay against a panel of 24 patient-derived viruses with high-level PI resistance, GS-8374 showed lower mean EC(50)s and lower fold resistance than any of the clinically approved PIs. Similar to other PIs, in vitro hepatic microsomal metabolism of GS-8374 was efficiently blocked by ritonavir, suggesting a potential for effective pharmacokinetic boosting in vivo. In summary, results from this broad in vitro pharmacological profiling indicate that GS-8374 is a promising candidate to be further assessed as a new antiretroviral agent with potential for clinical efficacy in both treatment-naïve and -experienced patients.
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