Journal
JOURNAL OF VIROLOGY
Volume 84, Issue 21, Pages 11235-11244Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01339-10
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Funding
- National Institute of Allergy and Infectious Diseases, National Institutes of Health [NIH], U.S. Department of Health and Human Services [HHSN272200700041C]
- NIH [AI076168, GM066682, GM082545]
- University of Utah
- Office of Biological and Environmental Research, U.S. Department of Energy
- National Center for Research Resources, NIH
- National Institute of General Medical Sciences
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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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