1. Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.
- Author
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Wu CH, Wang CJ, Chang CP, Cheng YC, Song JS, Jan JJ, Chou MC, Ke YY, Ma J, Wong YC, Hsieh TC, Tien YC, Gullen EA, Lo CF, Cheng CY, Liu YW, Sadani AA, Tsai CH, Hsieh HP, Tsou LK, and Shia KS
- Subjects
- Animals, CCR5 Receptor Antagonists chemical synthesis, CCR5 Receptor Antagonists chemistry, Cell Line, Dose-Response Relationship, Drug, HIV Fusion Inhibitors chemical synthesis, HIV Fusion Inhibitors chemistry, HIV Infections virology, HIV-1 metabolism, Humans, Male, Mice, Mice, Inbred C57BL, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Molecular Structure, Receptors, CXCR4 metabolism, Structure-Activity Relationship, CCR5 Receptor Antagonists pharmacology, HIV Fusion Inhibitors pharmacology, HIV Infections drug therapy, HIV-1 drug effects, Receptors, CXCR4 antagonists & inhibitors, Virus Internalization drug effects
- Abstract
Motivated by the pivotal role of CXCR4 as an HIV entry co-receptor, we herein report a de novo hit-to-lead effort on the identification of subnanomolar purine-based CXCR4 antagonists against HIV-1 infection. Compound 24, with an EC50 of 0.5 nM against HIV-1 entry into host cells and an IC50 of 16.4 nM for inhibition of radioligand stromal-derived factor-1α (SDF-1α) binding to CXCR4, was also found to be highly selective against closely related chemokine receptors. We rationalized that compound 24 complementarily interacted with the critical CXCR4 residues that are essential for binding to HIV-1 gp120 V3 loop and subsequent viral entry. Compound 24 showed a 130-fold increase in anti-HIV activity compared to that of the marketed CXCR4 antagonist, AMD3100 (Plerixafor), whereas both compounds exhibited similar potency in mobilization of CXCR4(+)/CD34(+) stem cells at a high dose. Our study offers insight into the design of anti-HIV therapeutics devoid of major interference with SDF-1α function.
- Published
- 2015
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