A dePEGylated Lipopeptide-Based Pan-Coronavirus Fusion Inhibitor Exhibits Potent and Broad-Spectrum Anti-HIV-1 Activity without Eliciting Anti-PEG Antibodies

Ling Xu; Chao Wang; Wei Xu; Lixiao Xing; Jie Zhou; Jing Pu; Mingming Fu; Lu Lu; Shibo Jiang; Qian Wang

doi:10.3390/ijms24119779

A dePEGylated Lipopeptide-Based Pan-Coronavirus Fusion Inhibitor Exhibits Potent and Broad-Spectrum Anti-HIV-1 Activity without Eliciting Anti-PEG Antibodies

Int J Mol Sci. 2023 Jun 5;24(11):9779. doi: 10.3390/ijms24119779.

Authors

Ling Xu¹, Chao Wang², Wei Xu¹, Lixiao Xing¹, Jie Zhou¹, Jing Pu¹, Mingming Fu¹, Lu Lu¹, Shibo Jiang¹, Qian Wang¹

Affiliations

¹ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.

Abstract

We previously identified a lipopeptide, EK1C4, by linking cholesterol to EK1, a pan-CoV fusion inhibitory peptide via a polyethylene glycol (PEG) linker, which showed potent pan-CoV fusion inhibitory activity. However, PEG can elicit antibodies to PEG in vivo, which will attenuate its antiviral activity. Therefore, we designed and synthesized a dePEGylated lipopeptide, EKL1C, by replacing the PEG linker in EK1C4 with a short peptide. Similar to EK1C4, EKL1C displayed potent inhibitory activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other coronaviruses. In this study, we found that EKL1C also exhibited broad-spectrum fusion inhibitory activity against human immunodeficiency virus type 1 (HIV-1) infection by interacting with the N-terminal heptad repeat 1 (HR1) of viral gp41 to block six-helix bundle (6-HB) formation. These results suggest that HR1 is a common target for the development of broad-spectrum viral fusion inhibitors and EKL1C has potential clinical application as a candidate therapeutic or preventive agent against infection by coronavirus, HIV-1, and possibly other class I enveloped viruses.

Keywords: HIV-1; broad-spectrum fusion inhibitor; coronavirus; six-helix bundle.

MeSH terms

Anti-Retroviral Agents
COVID-19*
HIV Envelope Protein gp41
HIV Fusion Inhibitors* / pharmacology
HIV Infections*
HIV-1*
Humans
Lipopeptides / pharmacology
SARS-CoV-2

Substances

Lipopeptides
Anti-Retroviral Agents
HIV Envelope Protein gp41
HIV Fusion Inhibitors

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (92169112 to S.J.), the Program of Shanghai Municipal Science and Technology Major Project, and Shanghai Academic/Technology Research Leader (20XD1420300 to L.L.)