title: Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus.
abstract: 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.
authors.affiliation: Trimeris Inc., 3500 Paramount Parkway, Morrisville, NC 27560, USA. jdwyer@trimeris.com
authors.forename: John J
authors.initials: JJ
authors.lastname: Dwyer
authors.forename: Karen L
authors.initials: KL
authors.lastname: Wilson
authors.forename: Donna K
authors.initials: DK
authors.lastname: Davison
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Freel
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Seedorff
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Wring
authors.forename: Nicolai A
authors.initials: NA
authors.lastname: Tvermoes
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Matthews
authors.forename: Michael L
authors.initials: ML
authors.lastname: Greenberg
authors.forename: Mary K
authors.initials: MK
authors.lastname: Delmedico
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D055592:Biophysical Phenomena; D001703:Biophysics; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000187:drug effects*; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects*; D008252:Macaca fascicularis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011489:Protein Denaturation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D013696:Temperature
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D010455:Peptides; C544608:T2635 peptide; D000077560:Enfuvirtide