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

被引：212

作者：

Dwyer, John J. ^{[1
]}

Wilson, Karen L. ^{[1
]}

Davison, Donna K. ^{[1
]}

Freel, Stephanie A. ^{[1
]}

Seedorff, Jennifer E. ^{[1
]}

Wring, Stephen A. ^{[1
]}

Tvermoes, Nicolai A. ^{[1
]}

Matthews, Thomas J. ^{[1
]}

Greenberg, Michael L. ^{[1
]}

Delmedico, Mary K. ^{[1
]}

机构：

[1] Trimeris Inc, Morrisville, NC 27560 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2007年 / 104卷 / 31期

关键词：

coiled coil; gp41; HIV-1; viral entry; drug design;

D O I：

10.1073/pnas.0701478104

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 ttractive for further development.

引用

页码：12772 / 12777

页数：6

共 43 条

[1] Anatomy of hot spots in protein interfaces [J].