Design of Novel HIV-1/2 Fusion Inhibitors with High Therapeutic Efficacy in Rhesus Monkey Models

T-20 (enfuvirtide) is the only approved viral fusion inhibitor that is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection; however, it has relatively low antiviral activity and easily induces drug resistance. We recently reported a T-20-based lipopeptide fusion inhibitor...

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Veröffentlicht in:Journal of virology 2018-08, Vol.92 (16)
Hauptverfasser: Chong, Huihui, Xue, Jing, Zhu, Yuanmei, Cong, Zhe, Chen, Ting, Guo, Yan, Wei, Qiang, Zhou, Yusen, Qin, Chuan, He, Yuxian
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Sprache:eng
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Zusammenfassung:T-20 (enfuvirtide) is the only approved viral fusion inhibitor that is used for the treatment of human immunodeficiency virus type 1 (HIV-1) infection; however, it has relatively low antiviral activity and easily induces drug resistance. We recently reported a T-20-based lipopeptide fusion inhibitor (LP-40) showing improved anti-HIV activity (X. Ding et al., J Virol 91:e00831-17, 2017, https://doi.org/10.1128/JVI.00831-17). In this study, we designed LP-50 and LP-51 by refining the structure and function of LP-40. The two new lipopeptides showed dramatically enhanced secondary structure and binding stability and were exceptionally potent inhibitors of HIV-1, HIV-2, simian immunodeficiency virus (SIV), and chimeric simian-human immunodeficiency virus (SHIV), with mean 50% inhibitory concentrations (IC s) in the very low picomolar range. They also exhibited dramatically increased potencies in inhibiting a panel of T-20- and LP-40-resistant mutant viruses. In line with their data, LP-50 and LP-51 exhibited extremely potent and long-lasting anti-HIV activities in rhesus monkeys: serum dilution peaks that inhibited 50% of virus infection were >15,200-fold higher than those for T-20 and LP-40. Low-dose, short-term monotherapy of LP-51 could sharply reduce viral loads to undetectable levels in acutely and chronically SHIV infected monkey models. To our knowledge, LP-50 and LP-51 are the most potent and broad HIV-1/2 and SIV fusion inhibitors, which can be developed for clinical use and can serve as tools for exploration of the mechanisms of viral entry and inhibition. T-20 remains the only membrane fusion inhibitor available for the treatment of viral infection, but its relatively low anti-HIV activity and genetic barrier for drug resistance have significantly limited its clinical application. Here we report two new lipopeptide-based fusion inhibitors (LP-50 and LP-51) showing extremely potent inhibitory activities against diverse HIV-1, HIV-2, SIV, and T-20-resistant variants. Promisingly, both inhibitors exhibited potent and long-lasting anti-HIV activity and could efficiently suppress viral loads to undetectable levels in SHIV-infected monkey models. We believe that LP-50 and LP-51 are the most potent and broad-spectrum fusion inhibitors known to date and thus have high potential for clinical development.
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.00775-18