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Lipopeptide-based pan-CoV fusion inhibitors potently inhibit HIV-1 infection

Class I enveloped viruses, such as human immunodeficiency virus type 1 (HIV-1) and highly pathogenic human coronaviruses (HCoVs), including severe acute respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and Middle East respiratory syndrome coronavirus (MERS-CoV), have posed serious threats to global public health and economy [1]. Therefore, development of broad-spectrum antivirals is urgently needed. During the fusion process of these class Ι enveloped viruses, an important and common feature is the formation of a six-helical bundle (6-HB) core structure by the heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains to bring viral and cellular membranes into close proximity for fusion [2]. In previous studies, we identified the first pan-CoV fusion inhibitory peptide (EK1) and lipopeptides (e.g., EK1C4) with potent inhibitory activity against infection by divergent HCoVs, including SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-229E, and HCoV-NL63 [[3], [4], [5]]. Crystallographic analysis has revealed that these pan-CoV fusion inhibitory peptides possess sufficient structural plasticity to access and interact with the HR1 trimer from different HCoVs, thus blocking their fusion with host cells [[3], [4], [5]]. In this study, we evaluated the potential inhibitory activity of these pan-CoV fusion inhibitory peptides and lipopeptides on HIV-1 infection, with the HIV-1 fusion inhibitory peptide T20 (enfuvirtide) as a control. We first used a cell-cell fusion assay to evaluate the inhibitory activity of EK1 peptide and EK1-lipopeptides (Fig. 1A) on fusion between the HIV-1IIIB chronically infected H9 (H9/HIV-1IIIB) cells and target cells (TZM-bl). As shown in Figure 1B, the peptides without lipid conjugation, EK1 and EK1C0, exhibited weak or no inhibitory activity on cell-cell fusion at the concentration up to 5,000 nM, respectively, while all 7 cholesterol-conjugated EK1-lipopeptides (EK1C1 to EK1C7) showed potent inhibitory activity on cell-cell fusion with half maximal inhibitory concentration (IC50) ranging from 65 to 862 nM. The C16-conjugated EK1-lipopeptide (EK1P1A) had moderate inhibitory activity with an IC50 of 1,932 nM. This result suggests that the cholesterol-conjugated pan-CoV fusion inhibitory lipopeptides also possess highly potent inhibitory activity against HIV-1 Env-mediated membrane fusion.

Figure 1. Potent HIV-1 fusion inhibitory activity of pan-CoV fusion inhibitory lipopeptides. (A) Sequence of EK1-lipopeptides with potential anti-HIV-1 activity; (B) Inhibitory activity of EK1-lipopeptides against cell-cell fusion between H9/HIV-1IIIB (effector) cells and TZM-bl (target) cells; (C) Inhibitory activity of EK1-lipopeptides against HIV-1Bal PsV entry into U87 cells; (D) Inhibition of HIV-1Bal replication by EK1C2A and cytotoxicity on M7 cells using ELISA for p24 and cytotoxic assay, respectively; (E) Inhibition of HIV-1IIIB replication by EK1C2A using ELISA for detection of p24 and cytotoxicity of EK1C2A on MT-2 cells with a cytotoxic assay. (F) Inhibitory activity of EK1C2A against infection by HIV-1 clinical isolates and T20-or T2635-resistant strains. Each sample was tested in triplicate, and the experiment was repeated at least twice. Data from a representative experiment are shown as means with standard deviation.

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