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A Peptide-Based HIV-1 Fusion Inhibitor with Two Tail-Anchors and Palmitic Acid Exhibits Substantially Improved In Vitro and Ex Vivo Anti-HIV-1 Activity and Prolonged In Vivo Half-Life

1,2,†, 2,†, 2, 1, 1, 3, 1,* and 1,2,3,*
1
Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, 130 Dong An Rd., Xuhui District, Shanghai 200032, China
2
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA
3
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(6), 1134; https://doi.org/10.3390/molecules24061134
Received: 26 February 2019 / Revised: 19 March 2019 / Accepted: 19 March 2019 / Published: 21 March 2019
(This article belongs to the Special Issue Bioactive Peptides—From Therapy to Nutrition)
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Abstract

Enfuvirtide (T20) is the first U.S. FDA-approved HIV fusion inhibitor-based anti-HIV drug. Its clinical application is limited because of its low potency and short half-life. We previously reported that peptide HP23-E6-IDL, containing both N- and C-terminal anchor-tails, exhibited stronger potency and a better resistance profile than T20. Here we designed an analogous peptide, YIK, by introducing a mutation, T639I, and then a lipopeptide, YIK-C16, by adding palmitic acid (C16) at the C-terminus of YIK. We found that YIK-C16 was 4.4- and 3.6-fold more potent than HP23-E6-IDL and YIK against HIV-1IIIB infection and 13.3- and 10.5-fold more effective than HP23-E6-IDL and YIK against HIV-1Bal infection, respectively. Consistently, the ex vivo anti-HIV-1IIIB activity, as determined by the highest dilution-fold of the serum causing 50% inhibition of HIV-1 infection, of YIK-C16 in the sera of pretreated mice was remarkably higher than that of YIK or HP23-E6-IDL. The serum half-life (t1/2 = 5.9 h) of YIK-C16 was also significantly longer than that of YIK (t1/2 = 1.3 h) and HP23-E6-IDL (t1/2 = 1.0 h). These results suggest that the lipopeptide YIK-C16 shows promise for further development as a new anti-HIV drug with improved anti-HIV-1 activity and a prolonged half-life. View Full-Text
Keywords: HIV-1; gp41; fusion inhibitor; six-helix bundle; peptide; palmitic acid HIV-1; gp41; fusion inhibitor; six-helix bundle; peptide; palmitic acid
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Su, S.; Rasquinha, G.; Du, L.; Wang, Q.; Xu, W.; Li, W.; Lu, L.; Jiang, S. A Peptide-Based HIV-1 Fusion Inhibitor with Two Tail-Anchors and Palmitic Acid Exhibits Substantially Improved In Vitro and Ex Vivo Anti-HIV-1 Activity and Prolonged In Vivo Half-Life. Molecules 2019, 24, 1134.

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