ArticleThe Journal of biological chemistry2009
Design of peptide-based inhibitors for human immunodeficiency virus type 1 strains resistant to T-20.
Article in The Journal of biological chemistry, 2009. 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, 42 citations in OpenAlex.
- Identification and structure-activity relationship analysis of minimal fusion inhibitors targeting measles virus F protein.RSC medicinal chemistry · 2026Article
- Structural Basis of Peptide-Based Antimicrobial Inhibition of a Resistance-Nodulation-Cell Division Multidrug Efflux Pump.Microbiology spectrum · 2022Article
- Structural and Functional Characterization of the Secondary Mutation N126K Selected by Various HIV-1 Fusion Inhibitors.Viruses · 2020Article
- Sulfono-γ-AA modified peptides that inhibit HIV-1 fusion.Organic & biomolecular chemistry · 2018Article
- AVP-IC50 Pred: Multiple machine learning techniques-based prediction of peptide antiviral activity in terms of half maximal inhibitory concentration (IC50).Biopolymers · 2015Article
- Mechanism of HIV-1 Resistance to Short-Peptide Fusion Inhibitors Targeting the Gp41 Pocket.Journal of virology · 2015Article
- Modular assembly of dimeric HIV fusion inhibitor peptides with enhanced antiviral potency.Bioorganic & medicinal chemistry letters · 2013Article
- HIV-1 resistance mechanism to an electrostatically constrained peptide fusion inhibitor that is active against T-20-resistant strains.Antimicrobial agents and chemotherapy · 2013Article
- Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design.The international journal of biochemistry & cell biology · 2013Article
- Review
- Potent anti-HIV-1 activity of N-HR-derived peptides including a deep pocket-forming region without antagonistic effects on T-20.Antiviral chemistry & chemotherapy · 2011Article
- Increasing hydrophobicity of residues in an anti-HIV-1 Env peptide synergistically improves potency.Biophysical journal · 2011Article
- Susceptibility of HIV-1 subtypes B', CRF07_BC and CRF01_AE that are predominantly circulating in China to HIV-1 entry inhibitors.PloS one · 2011Article
- In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor.The Journal of biological chemistry · 2011Article
- Resistance profiles of novel electrostatically constrained HIV-1 fusion inhibitors.The Journal of biological chemistry · 2010Article
- Discovery of entry inhibitors for HIV-1 via a new de novo protein design framework.Biophysical journal · 2010Article
- Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Origins of resistance to the HIVgp41 viral entry inhibitor T20.Biochemistry · 2010Article
- Computational methods for de novo protein design and its applications to the human immunodeficiency virus 1, purine nucleoside phosphorylase, ubiquitin specific protease 7, and histone demethylases.Current drug targets · 2010Review
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
Abstract
Enfuvirtide (T-20) is a fusion inhibitor that suppresses replication of human immunodeficiency virus (HIV) variants with multi-drug resistance to reverse transcriptase and protease inhibitors. It is a peptide derived from the C-terminal heptad repeat (C-HR) of HIV-1 gp41, and it prevents interactions between the C-HR and the N-terminal HR (N-HR) of gp41, thus interfering with conformational changes that are required for viral fusion. However, prolonged therapies with T-20 result in the emergence of T-20-resistant strains that contain primary mutations such as N43D in the N-HR of gp41 (where T-20 and C-HR bind) that help the virus escape at a fitness cost. Such variants often go on to acquire a secondary mutation, S138A, in the C-HR of gp41 region that corresponds to the sequence of T-20. We demonstrate here that the role of S138A is to compensate for the impaired fusion kinetics of HIV-1s carrying primary mutations that abrogate binding of T-20. To preempt this escape strategy, we designed a modified T-20 variant containing the S138A substitution and showed that it is a potent inhibitor of both T-20-sensitive and T-20-resistant viruses. Circular dichroism analysis revealed that the S138A provided increased stability of the 6-helix bundle. We validated our approach on another fusion inhibitor, C34. In this case, we designed a variant of C34 with the secondary escape mutation N126K and showed that it can effectively inhibit replication of C34-resistant HIV-1. These results prove that it is possible to design improved peptide-based fusion inhibitors that are efficient against a major mechanism of drug resistance.
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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.