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Molecules 2017, 22(11), 1996; doi:10.3390/molecules22111996

Adding an Artificial Tail—Anchor to a Peptide-Based HIV-1 Fusion Inhibitor for Improvement of Its Potency and Resistance Profile

1
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1
,
1
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2
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1,* and 1,2,3,*
1
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences & Shanghai Public Health Clinical Center, Fudan University, 130 Dong An Rd., Xuhui District, Shanghai 200032, China
2
Key Laboratory of Reproduction Regulation of National Population and Family Planning Commission, The Shanghai Institute of Planned Parenthood Research, Institute of Reproduction and Development, Fudan University, Shanghai 200032, China
3
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
*
Authors to whom correspondence should be addressed.
Received: 15 October 2017 / Revised: 10 November 2017 / Accepted: 16 November 2017 / Published: 20 November 2017
(This article belongs to the Special Issue Peptide Therapeutics)
View Full-Text   |   Download PDF [3265 KB, uploaded 20 November 2017]   |  

Abstract

Peptides derived from the C-terminal heptad repeat (CHR) of human immunodeficiency virus type 1 (HIV-1) envelope protein transmembrane subunit gp41, such as T20 (enfuvirtide), can bind to the N-terminal heptad repeat (NHR) of gp41 and block six-helix bundle (6-HB) formation, thus inhibiting HIV-1 fusion with the target cell. However, clinical application of T20 is limited because of its low potency and genetic barrier to resistance. HP23, the shortest CHR peptide, exhibits better anti-HIV-1 activity than T20, but the HIV-1 strains with E49K mutations in gp41 will become resistant to it. Here, we modified HP23 by extending its C-terminal sequence using six amino acid residues (E6) and adding IDL (Ile-Asp-Leu) to the C-terminus of E6, which is expected to bind to the shallow pocket in the gp41 NHR N-terminal region. The newly designed peptide, designated HP23-E6-IDL, was about 2- to 16-fold more potent than HP23 against a broad spectrum of HIV-1 strains and more than 12-fold more effective against HIV-1 mutants resistant to HP23. These findings suggest that addition of an anchor–tail to the C-terminus of a CHR peptide will allow binding with the pocket in the gp41 NHR that may increase the peptide’s antiviral efficacy and its genetic barrier to resistance. View Full-Text
Keywords: HIV; gp41; fusion inhibitor; six-helix bundle; peptide HIV; gp41; fusion inhibitor; six-helix bundle; peptide
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Su, S.; Ma, Z.; Hua, C.; Li, W.; Lu, L.; Jiang, S. Adding an Artificial Tail—Anchor to a Peptide-Based HIV-1 Fusion Inhibitor for Improvement of Its Potency and Resistance Profile. Molecules 2017, 22, 1996.

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