Skip to main content
Journal cover image

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

Publication ,  Journal Article
Dwyer, JJ; Wilson, KL; Davison, DK; Freel, SA; Seedorff, JE; Wring, SA; Tvermoes, NA; Matthews, TJ; Greenberg, ML; Delmedico, MK
Published in: Proceedings of the National Academy of Sciences of the United States of America
July 2007

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

July 2007

Volume

104

Issue

31

Start / End Page

12772 / 12777

Related Subject Headings

  • Temperature
  • Protein Structure, Secondary
  • Protein Folding
  • Protein Denaturation
  • Peptides
  • Peptide Fragments
  • Molecular Sequence Data
  • Macaca fascicularis
  • HIV-1
  • HIV Infections
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Dwyer, J. J., Wilson, K. L., Davison, D. K., Freel, S. A., Seedorff, J. E., Wring, S. A., … Delmedico, M. K. (2007). Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proceedings of the National Academy of Sciences of the United States of America, 104(31), 12772–12777. https://doi.org/10.1073/pnas.0701478104
Dwyer, John J., Karen L. Wilson, Donna K. Davison, Stephanie A. Freel, Jennifer E. Seedorff, Stephen A. Wring, Nicolai A. Tvermoes, Thomas J. Matthews, Michael L. Greenberg, and Mary K. Delmedico. “Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus.Proceedings of the National Academy of Sciences of the United States of America 104, no. 31 (July 2007): 12772–77. https://doi.org/10.1073/pnas.0701478104.
Dwyer JJ, Wilson KL, Davison DK, Freel SA, Seedorff JE, Wring SA, et al. Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jul;104(31):12772–7.
Dwyer, John J., et al. “Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus.Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 31, July 2007, pp. 12772–77. Epmc, doi:10.1073/pnas.0701478104.
Dwyer JJ, Wilson KL, Davison DK, Freel SA, Seedorff JE, Wring SA, Tvermoes NA, Matthews TJ, Greenberg ML, Delmedico MK. Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proceedings of the National Academy of Sciences of the United States of America. 2007 Jul;104(31):12772–12777.
Journal cover image

Published In

Proceedings of the National Academy of Sciences of the United States of America

DOI

EISSN

1091-6490

ISSN

0027-8424

Publication Date

July 2007

Volume

104

Issue

31

Start / End Page

12772 / 12777

Related Subject Headings

  • Temperature
  • Protein Structure, Secondary
  • Protein Folding
  • Protein Denaturation
  • Peptides
  • Peptide Fragments
  • Molecular Sequence Data
  • Macaca fascicularis
  • HIV-1
  • HIV Infections