Multitargeted drug design strategy for discovery of short-peptide-based HIV-1 entry inhibitors with high potency

Chao Wang; Huan Wang; Xinling Wang; Lujia Sun; Qian Wang; Qing Li; Ruiying Liang; Dou Dou; Fei Yu; Lu Lu; Shibo Jiang

doi:10.1016/j.ejmech.2023.115294

Multitargeted drug design strategy for discovery of short-peptide-based HIV-1 entry inhibitors with high potency

Eur J Med Chem. 2023 Apr 5:252:115294. doi: 10.1016/j.ejmech.2023.115294. Epub 2023 Mar 16.

Authors

Chao Wang¹, Huan Wang², Xinling Wang³, Lujia Sun³, Qian Wang³, Qing Li², Ruiying Liang⁴, Dou Dou⁴, Fei Yu⁵, Lu Lu⁶, Shibo Jiang⁷

Affiliations

¹ State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China. Electronic address: chaow301@sina.com.
² State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing, 100850, China.
³ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, 131 Dong an Road, Shanghai, 200032, China.
⁴ Hebei Center for Wildlife Health, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China.
⁵ Hebei Center for Wildlife Health, College of Life Sciences, Hebei Agricultural University, Baoding, 071001, China. Electronic address: shmyf@hebau.edu.cn.
⁶ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, 131 Dong an Road, Shanghai, 200032, China. Electronic address: lul@fudan.edu.cn.
⁷ Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Shanghai Institute of Infectious Diseases and Biosecurity, Fudan University, 131 Dong an Road, Shanghai, 200032, China. Electronic address: shibojiang@fudan.edu.cn.

PMID: 36944281
DOI: 10.1016/j.ejmech.2023.115294

Abstract

The development of short-peptide-based inhibitors to prevent HIV-1 entry into the host cell has been rewarded with limited success. Herein, we report a multitarget-directed ligand strategy to generate a series of short-peptide HIV-1 entry inhibitors that integrated the pharmacological activities of a peptide fusion inhibitor able to disrupt HIV-1 gp41 glycoprotein hexameric coiled-coil assembly and a small-molecule CCR5 antagonist that blocks the interaction between HIV-1 and its coreceptor. Among these inhibitors, dual-target 23-residue peptides SP12T and SP12L displayed dramatically increased inhibitory activities against HIV-1 replication as compared to the marketed 36-residue peptide T20. Moreover, results suggested that SP12T and SP12L successfully performed a dual-targeting mechanism. It can be concluded that these short-peptide-based HIV-1 entry inhibitors have potential for further development as candidates for a novel multitarget therapy to treat HIV-1 infection.

Keywords: CCR5; Entry inhibitors; HIV-1; Multi-target-directed ligands; gp41.

MeSH terms

Drug Design
HIV Envelope Protein gp41
HIV Fusion Inhibitors* / chemistry
HIV Fusion Inhibitors* / pharmacology
HIV Infections*
HIV-1*
Humans
Peptide Fragments / chemistry
Peptides / pharmacology

Substances

Peptide Fragments
HIV Envelope Protein gp41
HIV Fusion Inhibitors
Peptides