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
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 a...
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MDPI AG
2019-03-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/6/1134 |
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| author | Shan Su Giselle Rasquinha Lanying Du Qian Wang Wei Xu Weihua Li Lu Lu Shibo Jiang |
| author_facet | Shan Su Giselle Rasquinha Lanying Du Qian Wang Wei Xu Weihua Li Lu Lu Shibo Jiang |
| author_sort | Shan Su |
| collection | DOAJ |
| description | 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-1<sub>IIIB</sub> infection and 13.3- and 10.5-fold more effective than HP23-E6-IDL and YIK against HIV-1<sub>Bal</sub> infection, respectively. Consistently, the ex vivo anti-HIV-1<sub>IIIB</sub> 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 (t<sub>1/2</sub> = 5.9 h) of YIK-C16 was also significantly longer than that of YIK (t<sub>1/2</sub> = 1.3 h) and HP23-E6-IDL (t<sub>1/2</sub> = 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. |
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| series | Molecules |
| spelling | doaj.art-0d9259fe795f46e29af9ad6f038167942022-12-22T02:29:13ZengMDPI AGMolecules1420-30492019-03-01246113410.3390/molecules24061134molecules24061134A 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-LifeShan Su0Giselle Rasquinha1Lanying Du2Qian Wang3Wei Xu4Weihua Li5Lu Lu6Shibo Jiang7Key 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, ChinaLindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USALindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USAKey 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, ChinaKey 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, ChinaNHC Key Laboratory of Reproduction Regulation, Shanghai Institute of Planned Parenthood Research, Fudan University, Shanghai 200032, ChinaKey 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, ChinaKey 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, ChinaEnfuvirtide (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-1<sub>IIIB</sub> infection and 13.3- and 10.5-fold more effective than HP23-E6-IDL and YIK against HIV-1<sub>Bal</sub> infection, respectively. Consistently, the ex vivo anti-HIV-1<sub>IIIB</sub> 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 (t<sub>1/2</sub> = 5.9 h) of YIK-C16 was also significantly longer than that of YIK (t<sub>1/2</sub> = 1.3 h) and HP23-E6-IDL (t<sub>1/2</sub> = 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.https://www.mdpi.com/1420-3049/24/6/1134HIV-1gp41fusion inhibitorsix-helix bundlepeptidepalmitic acid |
| spellingShingle | Shan Su Giselle Rasquinha Lanying Du Qian Wang Wei Xu Weihua Li Lu Lu Shibo Jiang 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 HIV-1 gp41 fusion inhibitor six-helix bundle peptide palmitic acid |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | HIV-1 gp41 fusion inhibitor six-helix bundle peptide palmitic acid |
| url | https://www.mdpi.com/1420-3049/24/6/1134 |
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