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

Abstract

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 (IC50s) 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 in vitro data, LP-50 and LP-51 exhibited extremely potent and long-lasting ex vivo 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.IMPORTANCE 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 ex vivo 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.

• Authors: Huihui Chong, Jing Xue, Yuanmei Zhu, Zhe Cong, Ting Chen, Yan Guo, Qiang Wei, Yusen Zhou, Chuan Qin, Yuxian He
• Journal: Journal of virology (J Virol) Vol. 92 Issue 16 (08 15 2018) ISSN: 1098-5514 [Electronic] United States
• PMID: 29899103 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 American Society for Microbiology.

Chemical References

• Antiviral Agents
• Lipopeptides

Topics

• Animals
• Antiviral Agents (administration & dosage, chemical synthesis, pharmacology)
• HIV-1 (drug effects, physiology)
• HIV-2 (drug effects, physiology)
• Inhibitory Concentration 50
• Lipopeptides (administration & dosage, chemical synthesis, pharmacology)
• Macaca mulatta
• Simian Acquired Immunodeficiency Syndrome (drug therapy)
• Simian Immunodeficiency Virus
• Treatment Outcome
• Viral Load
• Virus Internalization (drug effects)