A Novel CXCR4 Targeting Protein SDF-1/54 as an HIV-1 Entry Inhibitor
Suiyi Tan,
Wenjuan Li,
Zhaofeng Li,
Yujing Li,
Jiangyan Luo,
Liangzhentian Yu,
Jie Yang,
Mengjie Qiu,
Hongyan Cheng,
Wei Xu,
Shibo Jiang,
Lu Lu,
Shuwen Liu,
Weifeng Ma
Affiliations
Suiyi Tan
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Wenjuan Li
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Zhaofeng Li
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Yujing Li
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China
Jiangyan Luo
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China
Liangzhentian Yu
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China
Jie Yang
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China
Mengjie Qiu
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Hongyan Cheng
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Wei Xu
Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China
Shibo Jiang
Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China
Lu Lu
Key Laboratory of Medical Molecular Virology of Ministries of Education & Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China
Shuwen Liu
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
Weifeng Ma
Department of Microbiology, School of Public Health, Southern Medical University, Guangzhou 510515, China
CXC chemokine receptor 4 (CXCR4) is a co-receptor for HIV-1 entry into target cells. Its natural ligand, the chemokine SDF-1, inhibits viral entry mediated by this receptor. However, the broad expression pattern of CXCR4 and its critical roles in various physiological and pathological processes indicate that the direct application of SDF-1 as an entry inhibitor might have severe consequences. Previously, we constructed an effective SDF-1 mutant, SDF-1/54, by deleting the α-helix of the C-terminal functional region of SDF-1. Of note, SDF-1/54 shows remarkable decreased chemotoxic ability, but maintains a similar binding affinity to CXCR4, suggesting SDF-1/54 might better serve as a CXCR4 inhibitor. Here, we found that SDF-1/54 exhibited potent antiviral activity against various X4 HIV-1 strains, including the infectious clone HIV-1 NL4-3, laboratory-adapted strain HIV-1 IIIB, clinical isolates and even drug-resistant strains. By using time-of-addition assay, non-infectious and infectious cell−cell fusion assay and CXCR4 internalization assay, we demonstrated SDF-1/54 is an HIV-1 entry inhibitor. A combination of SDF-1/54 with several antiretroviral drugs exhibited potent synergistic anti-HIV-1 activity. Moreover, SDF-1/54 was stable and its anti-HIV-1 activity was not significantly affected by the presence of seminal fluid, vaginal fluid simulant and human serum albumin. SDF-1/54 showed limited in vitro cytotoxicity to lymphocytes and vaginal epithelial cells. Based on these findings, SDF-1/54 could have a therapeutic potential as an HIV-1 entry inhibitor.
