Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance.
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.
Welch
Brett D
BD
Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Rm. 4100, Salt Lake City, UT 84112-5650, USA.
Francis
J Nicholas
JN
Redman
Joseph S
JS
Paul
Suparna
S
Weinstock
Matthew T
MT
Reeves
Jacqueline D
JD
Lie
Yolanda S
YS
Whitby
Frank G
FG
Eckert
Debra M
DM
Hill
Christopher P
CP
Root
Michael J
MJ
Kay
Michael S
MS
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
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010455:Peptides; D010447:Peptide Hydrolases