key: cord-0017524-lfft6xcp
authors: Lan, Qiaoshuai; Pu, Jing; Cai, Yanxing; Zhou, Jie; Wang, Lijue; Jiao, Fanke; Xu, Wei; Wang, Qian; Xia, Shuai; Lu, Lu; Jiang, Shibo
title: Lipopeptide-based pan-CoV fusion inhibitors potently inhibit HIV-1 infection
date: 2021-05-20
journal: Microbes Infect
DOI: 10.1016/j.micinf.2021.104840
sha: a70041727ee07da7d6e62fd2ad7d281913f4143e
doc_id: 17524
cord_uid: lfft6xcp

nan

Class I enveloped viruses, such as human immunodeficiency virus type 1 (HIV-1) 13 and highly pathogenic human coronaviruses (HCoVs), including severe acute 14 respiratory syndrome coronavirus (SARS-CoV), SARS-CoV-2, and Middle East 15 respiratory syndrome coronavirus (MERS-CoV), have posed serious threats to global 16 public health and economy [1] . Therefore, development of broad-spectrum antivirals 17 is urgently needed. 18

During the fusion process of these class Ι enveloped viruses, an important and 19 common feature is the formation of a six-helical bundle (6-HB) core structure by the 20 heptad repeat 1 (HR1) and heptad repeat 2 (HR2) domains to bring viral and cellular 21 membranes into close proximity for fusion [2] . In previous studies, we identified the 22 first pan-CoV fusion inhibitory peptide (EK1) and lipopeptides (e.g., EK1C4) with 23 potent inhibitory activity against infection by divergent HCoVs, including 24 SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-229E, and 25

HCoV-NL63 [3] [4] [5] . Crystallographic analysis has revealed that these pan-CoV fusion 26 inhibitory peptides possess sufficient structural plasticity to access and interact with In this study, we evaluated the potential inhibitory activity of these pan-CoV fusion 29 inhibitory peptides and lipopeptides on HIV-1 infection, with the HIV-1 fusion 30 inhibitory peptide T20 (enfuvirtide) as a control. 31

We first used a cell-cell fusion assay to evaluate the inhibitory activity of EK1 32 peptide and EK1-lipopeptides (Fig. 1A) on fusion between the HIV-1 IIIB chronically 33 infected H9 (H9/HIV-1 IIIB ) cells and target cells (TZM-bl). As shown in Figure 1B HIV-1 Bal replication in CEMx174 517 5.25 M7 cells with an IC 50 of 8.6 nM (Fig. 1D) . 58

It could also effectively inhibit HIV-1 IIIB infection in MT-2 cells with an IC 50 of 6 nM 59 (Fig.1E) . Moreover, EK1C2A had low or no detectable toxicity on MT-2 and 60

CEMx174 517 5.25 M7 cells in vitro ( Fig. 1D and 1E) . 

We declare no conflict of interest. 84 

Common Features of Enveloped Viruses and Implications for Immunogen Design 87 for Next-Generation Vaccines

Antivirals with common targets against highly pathogenic viruses

A pan-coronavirus fusion inhibitor 91 targeting the HR1 domain of human coronavirus spike

Fusion mechanism of 2019-nCoV and fusion 93 inhibitors targeting HR1 domain in spike protein

Inhibition of SARS-CoV-2 (previously 95 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike 96 protein that harbors a high capacity to mediate membrane fusion

ADS-J1 inhibits HIV-1 infection and membrane 98 fusion by targeting the highly conserved pocket in the gp41 NHR-trimer