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Exceptional Potency and Structural Basis of a T1249-Derived Lipopeptide Fusion Inhibitor against HIV-1, HIV-2, and Simian Immunodeficiency Virus.

Exceptional Potency and Structural Basis of a T1249-Derived Lipopeptide Fusion Inhibitor against HIV-1, HIV-2, and Simian Immunodeficiency Virus.
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Zhu Y, Zhang X, Ding X, Chong H, Cui S, He J, Wang X, He Y,


Zhu Y, Zhang X, Ding X, Chong H, Cui S, He J, Wang X, He Y, (click to view)

Zhu Y, Zhang X, Ding X, Chong H, Cui S, He J, Wang X, He Y,

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The Journal of biological chemistry 2018 02 07() pii jbc.RA118.001729
Abstract

Enfuvirtide (T20) is the only viral fusion inhibitor approved for clinical use, but it has relatively weak anti-HIV activity and easily induces drug resistance. In succession to T20, T1249 has been designed as a 39-mer peptide composed of amino acid sequences derived from HIV-1, HIV-2, and simian immunodeficiency virus (SIV); however, its development has been suspended due to formulation difficulties. We recently developed a T20-based lipopeptide (LP-40) showing greatly improved pharmaceutical properties. Here, we generated a T1249-based lipopeptide, termed LP-46, by replacing its C-terminal tryptophan-rich sequence with fatty acid. As compared to T20, T1249, and LP-40, the truncated LP-46 (31-mer) had dramatically increased activities in inhibiting a large panel of HIV-1 subtypes, with IC50 values approaching low picomolar (pM) concentrations. Also, LP-46 was an exceptionally potent inhibitor against HIV-2, SIV, and T20-resistant variants, and it displayed obvious synergistic effects with LP-40. Furthermore, we showed that LP-46 had increased helical stability and binding affinity with the target site. The crystal structure of LP-46 in complex with a target surrogate revealed its critical binding motifs underlying the mechanism of action. Interestingly, it was found that the introduced pocket-binding domain (PBD) in LP-46 did not interact with the gp41 pocket as expected; instead, it adopted a mode similar to that of LP-40. Therefore, our studies have provided an exceptionally potent and broad fusion inhibitor for developing new anti-HIV drugs, which can also serve as a tool to exploit the mechanisms of viral fusion and inhibition.

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