Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus.

Journal Article (Journal Article)

Enfuvirtide (ENF), the first approved fusion inhibitor (FI) for HIV, is a 36-aa peptide that acts by binding to the heptad repeat 1 (HR1) region of gp41 and preventing the interaction of the HR1 and HR2 domains, which is required for virus-cell fusion. Treatment-acquired resistance to ENF highlights the need to create FI therapeutics with activity against ENF-resistant viruses and improved durability. Using rational design, we have made a series of oligomeric HR2 peptides with increased helical structure and with exceptionally high HR1/HR2 bundle stability. The engineered peptides are found to be as much as 3,600-fold more active than ENF against viruses that are resistant to the HR2 peptides ENF, T-1249, or T-651. Passaging experiments using one of these peptides could not generate virus with decreased sensitivity, even after >70 days in culture, suggesting superior durability as compared with ENF. In addition, the pharmacokinetic properties of the engineered peptides were improved up to 100-fold. The potent antiviral activity against resistant viruses, the difficulty in generating resistant virus, and the extended half-life in vivo make this class of fusion inhibitor peptide attractive for further development.

Full Text

Duke Authors

Cited Authors

  • Dwyer, JJ; Wilson, KL; Davison, DK; Freel, SA; Seedorff, JE; Wring, SA; Tvermoes, NA; Matthews, TJ; Greenberg, ML; Delmedico, MK

Published Date

  • July 2007

Published In

Volume / Issue

  • 104 / 31

Start / End Page

  • 12772 - 12777

PubMed ID

  • 17640899

Pubmed Central ID

  • PMC1937542

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0701478104


  • eng