Design of a Potent D-Peptide HIV-1 Entry Inhibitor with a Strong Barrier to Resistance

作者：Welch Brett D; Francis J Nicholas; Redman Joseph S; Paul Suparna; Weinstock Matthew T; Reeves Jacqueline D; Lie Yolanda S; Whitby Frank G; Eckert Debra M; Hill Christopher P; Root Michael J; Kay Michael S^*

来源：Journal of Virology, 2010, 84(21): 11235-11244.

DOI：10.1128/JVI.01339-10

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.

• 出版日期2010-11