A Lipopeptide HIV-1/2 Fusion Inhibitor with Highly PotentIn Vitro,Ex Vivo, andIn VivoAntiviral Activity

Abstract

Peptides derived from the C-terminal heptad repeat (CHR) region of the human immunodeficiency virus type 1 (HIV-1) fusogenic protein gp41 are potent viral entry inhibitors, and currently, enfuvirtide (T-20) is the only one approved for clinical use; however, emerging drug resistance largely limits its efficacy. In this study, we generated a novel lipopeptide inhibitor, named LP-19, by integrating multiple design strategies, including an N-terminal M-T hook structure, an HIV-2 sequence, intrahelical salt bridges, and a membrane-anchoring lipid tail. LP-19 showed stable binding affinity and highly potent, broad, and long-lasting antiviral activity. In in vitro studies, LP-19 efficiently inhibited HIV-1-, HIV-2-, and simian immunodeficiency virus (SIV)-mediated cell fusion, viral entry, and infection, and it was highly active against diverse subtypes of primary HIV-1 isolates and inhibitor-resistant mutants. Ex vivo studies demonstrated that LP-19 exhibited dramatically increased anti-HIV activity and an extended half-life in rhesus macaques. In short-term monotherapy, LP-19 reduced viral loads to undetectable levels in acutely and chronically simian-human immunodeficiency virus (SHIV)-infected monkeys. Therefore, this study offers an ideal HIV-1/2 fusion inhibitor for clinical development and emphasizes the importance of the viral fusion step as a drug target. IMPORTANCE The peptide drug T-20 is the only viral fusion inhibitor in the clinic, which is used for combination therapy of HIV-1 infection; however, it requires a high dosage and easily induces drug resistance, calling for a new drug with significantly improved pharmaceutical profiles. Here, we have developed a short-lipopeptide-based fusion inhibitor, termed LP-19, which mainly targets the conserved gp41 pocket site and shows highly potent inhibitory activity against HIV-1, HIV-2, and even SIV isolates. LP-19 exhibits dramatically increased antiviral activity and an extended half-life in rhesus macaques, and it has potent therapeutic efficacy in SHIV-infected monkeys, highlighting its high potential as a new viral fusion inhibitor for clinical use.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

“… Importantly, anchoring C34 peptide on cell surface also enhance the peptide's stability, as the antiviral activity appeared to be persistent following extensive wash . Similar lipid peptide‐based HIV fusion inhibitors were reported . The dramatically enhanced inhibitory potency and stability, combined with the >300‐fold increase in plasma concentration, make this amphiphilic strategy attractive in blocking many other virus entry during infections.…”

Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion

“…However, the potent stability of SARS-CoV-2 6-HB structure might reduce the antiviral efficacy of EK1. Recently, numerous reports have shown that the lipidation strategy can effectively improve the antiviral activity of fusion inhibitory peptides, such as the ant-HIV-1 peptide LP-19, 18 and the anti-Nipah virus lipopeptides. 19 In order to improve the inhibitory activity of EK1, cholesterol (Chol) and palmitic acid (Palm) were covalently attached to the Cterminus of EK1 sequence under the help of a flexible polyethylene glycol (PEG) spacer, and the corresponding lipopeptides EK1C and EK1P were constructed, respectively ( Fig.…”

Antiviral peptides as promising therapeutic drugs

“…Among all the viruses causing human diseases, none has ever caused more concern worldwide than HIV, with more than 36 million people infected [139]. The currently available antiviral treatment targets four steps of the viral cycle: viral entry, reverse transcription, integration, and virion maturation [140]. However, since HIV-1 and HIV-2 have different evolutionary histories, sharing only 50% of genetic similarity, most antivirals are capable of inhibiting only HIV-1, and a few inhibit HIV-2 [141,142].…”

“…The results showed that LP-19 could inhibit HIV-1, -2 and SIV in much lower concentrations than 2P23, especially in the assay for inhibition of virus entry. The lipid conjugation strategy improved the peptide's binding stability and antiviral activity in both in vitro and ex vivo assays, providing a good candidate for drug development [140].…”