ArticleProceedings of the National Academy of Sciences of the United States of America2009
Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 124 papers.
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Who cites it
124 citing papers in PubMed, 210 citations in OpenAlex.
- A first-in-human study of the novel HIV-fusion inhibitor C34-PEGScientific reports · 2017Trial
- Antiviral Activity and Mucosal Safety of Novel Human-Milk-Inspired Antimicrobial Peptides.Pharmaceutics · 2026Article
- Article
- Nanobody-Based Bioconjugates as Potent and Broadly Active Inhibitors of HIV Entry.Journal of the American Chemical Society · 2026Article
- Structure-Guided Design of Peptide Inhibitors Targeting Class I Viral Fusion Proteins.Pathogens (Basel, Switzerland) · 2025Review
- The conformational epitope of a gp41-specific mucosal protective IgA binds to the HIV-1 envelope and neutralizes infection.Acta pharmacologica Sinica · 2025Article
- Single-molecule localisation microscopy approaches reveal envelope glycoprotein clusters in single-enveloped viruses: a potential functional role?Biochemical Society transactions · 2025Review
- Enhancing the solubility of SARS-CoV-2 inhibitors to increase future prospects for clinical development.Journal of virology · 2025Article
- Development of nebulized inhalation delivery for fusion-inhibitory lipopeptides to protect non-human primates against Nipah-Bangladesh infection.Antiviral research · 2025Article
- Structure and Function of the SARS-CoV-2 6-HB Fusion Core and Peptide-based Fusion Inhibitors: A Review.Current medicinal chemistry · 2025Review
- The Role of Peptides in Combatting HIV Infection: Applications and Insights.Molecules (Basel, Switzerland) · 2024Review
- Article
- Article
- Inactivation of cell-free HIV-1 by designing potent peptides based on mutations in the CD4 binding site.Medical & biological engineering & computing · 2024Article
- A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential.Nature communications · 2024Article
- Lipidization as a tool toward peptide therapeutics.Drug delivery · 2023Review
- Article
- Glycosylation and Lipidation Strategies: Approaches for Improving Antimicrobial Peptide Efficacy.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Strategies to improve the physicochemical properties of peptide-based drugs.Pharmaceutical research · 2023Review
- Will Peptides Help to Stop COVID-19?Biochemistry. Biokhimiia · 2022Review
64 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapy-experienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC(90) values 15- to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC(50) only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC(90) values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.