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Molecules. 2019 Mar 21;24(6). pii: E1134. doi: 10.3390/molecules24061134.

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.

Su S1,2, Rasquinha G3, Du L4, Wang Q5, Xu W6, Li W7, Lu L8, Jiang S9,10,11.

Author information

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. 14111010010@fudan.edu.cn.
2
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA. 14111010010@fudan.edu.cn.
3
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA. glr@outlook.com.
4
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA. ldu@nybc.org.
5
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. wang_qian@fudan.edu.cn.
6
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. xuwei0576@126.com.
7
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China. iamliweihua@foxmail.com.
8
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. lul@fudan.edu.cn.
9
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. shibojiang@fudan.edu.cn.
10
Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA. shibojiang@fudan.edu.cn.
11
NHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, China. shibojiang@fudan.edu.cn.

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.

KEYWORDS:

HIV-1; fusion inhibitor; gp41; palmitic acid; peptide; six-helix bundle

PMID:
30901967
DOI:
10.3390/molecules24061134
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