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J Virol. 2010 Nov;84(21):11235-44. doi: 10.1128/JVI.01339-10. Epub 2010 Aug 18.

Design of a potent D-peptide HIV-1 entry inhibitor with a strong barrier to resistance.

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Department of Biochemistry, University of Utah School of Medicine, 15 N. Medical Drive East, Rm. 4100, Salt Lake City, UT 84112-5650, USA.


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.

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