title: Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance.
abstract: The HIV gp41 N-trimer pocket region is an ideal viral target because it is extracellular, highly conserved, and essential for viral entry. Here, we report on the design of a pocket-specific D-peptide, PIE12-trimer, that is extraordinarily elusive to resistance and characterize its inhibitory and structural properties. D-peptides (peptides composed of D-amino acids) are promising therapeutic agents due to their insensitivity to protease degradation. PIE12-trimer was designed using structure-guided mirror-image phage display and linker optimization and is the first D-peptide HIV entry inhibitor with the breadth and potency required for clinical use. PIE12-trimer has an ultrahigh affinity for the gp41 pocket, providing it with a reserve of binding energy (resistance capacitor) that yields a dramatically improved resistance profile compared to those of other fusion inhibitors. These results demonstrate that the gp41 pocket is an ideal drug target and establish PIE12-trimer as a leading anti-HIV antiviral candidate.
authors: Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Rm. 4100, Salt Lake City, UT 84112-5650, USA.
authors: Brett D
authors: BD
authors: Welch
authors: J Nicholas
authors: JN
authors: Francis
authors: Joseph S
authors: JS
authors: Redman
authors: Suparna
authors: S
authors: Paul
authors: Matthew T
authors: MT
authors: Weinstock
authors: Jacqueline D
authors: JD
authors: Reeves
authors: Yolanda S
authors: YS
authors: Lie
authors: Frank G
authors: FG
authors: Whitby
authors: Debra M
authors: DM
authors: Eckert
authors: Christopher P
authors: CP
authors: Hill
authors: Michael J
authors: MJ
authors: Root
authors: Michael S
authors: MS
authors: Kay
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D024882:Drug Resistance, Viral; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors; D023581:HIV Fusion Inhibitors / Q000737:chemistry*; D010447:Peptide Hydrolases / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; D010447:Peptide Hydrolases