An Artificial Peptide-Based Bifunctional HIV-1 Entry Inhibitor That Interferes with Viral Glycoprotein-41 Six-Helix Bundle Formation and Antagonizes CCR5 on the Host Cell Membrane
Chao Wang,
Qing Li,
Lujia Sun,
Xinling Wang,
Huan Wang,
Wenpeng Zhang,
Jiahui Li,
Yang Liu,
Lu Lu,
Shibo Jiang
Affiliations
Chao Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Qing Li
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Lujia Sun
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
Xinling Wang
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
Huan Wang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Wenpeng Zhang
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Jiahui Li
State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Tai-Ping Road, Beijing 100850, China
Yang Liu
Key Laboratory of Structure-Based Drug Design and Discovery of the Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
Lu Lu
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
Shibo Jiang
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
Human immunodeficiency virus type 1 (HIV-1) is characterized by high variability and drug resistance. This has necessitated the development of antivirals with a new chemotype and therapy. We previously identified an artificial peptide with non-native protein sequence, AP3, with the potential to inhibit HIV-1 fusion through targeting hydrophobic grooves on the N-terminal heptad repeat trimer of viral glycoprotein gp41. Here, a small-molecule HIV-1 inhibitor targeting chemokine coreceptor CCR5 on the host cell was integrated into the AP3 peptide, producing a novel dual-target inhibitor with improved activity against multiple HIV-1 strains including those resistant to the currently used anti-HIV-1 drug enfuvirtide. Its superior antiviral potency in comparison with the respective pharmacophoric moieties is in consonance with the dual binding of viral gp41 and host factor CCR5. Therefore, our work provides a potent artificial peptide-based bifunctional HIV-1 entry inhibitor and highlights the multitarget-directed ligands approach in the development of novel therapeutic anti-HIV-1 agents.
