Open AccessDesign of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus
Author(s) -
John J. Dwyer,
Karen L. Wilson,
Donna K. Davison,
Stephanie A. Freel,
Jennifer E. Seedorff,
Stephen A. Wring,
Nicolai A. Tvermoes,
Thomas J. Matthews,
Michael Greenberg,
Mary K. Delmedico
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0701478104
Subject(s) - enfuvirtide , gp41 , heptad repeat , peptide , virus , virology , in vivo , lipid bilayer fusion , biology , in vitro , chemistry , peptide sequence , biochemistry , immunology , genetics , antigen , gene , epitope
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-lifein vivo make this class of fusion inhibitor peptide attractive for further development.