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Title: Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy

Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20’s antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.
Authors:
 [1] ;  [2] ;  [2] ;  [1] ;  [1] ;  [1] ;  [1] ;  [3] ;  [1] ;  [4] ;  [4] ;  [4] ;  [1] ;  [1] ;  [5] ;  [4] ;  [1] ;  [2] ;  [3]
  1. Fudan Univ., Shanghai (China)
  2. Chinese Academy of Sciences (CAS), Beijing (China)
  3. Fudan Univ., Shanghai (China); New York Blood Center, New York, NY (United States). Lindsley F. Kimball Research Inst.
  4. Beijing Inst. of Pharmacology & Toxicology (China)
  5. New York Blood Center, New York, NY (United States). Lindsley F. Kimball Research Inst.
Publication Date:
OSTI Identifier:
1214788
Grant/Contract Number:
AC02-06CH11357
Type:
Accepted Manuscript
Journal Name:
Scientific Reports
Additional Journal Information:
Journal Volume: 5; Journal ID: ISSN 2045-2322
Publisher:
Nature Publishing Group
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES