title: Function-oriented development of CXCR4 antagonists as selective human immunodeficiency virus (HIV)-1 entry inhibitors.
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.
authors.affiliation: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes , Miaoli County 35053, Taiwan, R.O.C.
authors.forename: Chien-Huang
authors.initials: CH
authors.lastname: Wu
authors.forename: Chuan-Jen
authors.initials: CJ
authors.lastname: Wang
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Chang
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
authors.forename: Jen-Shin
authors.initials: JS
authors.lastname: Song
authors.forename: Jiing-Jyh
authors.initials: JJ
authors.lastname: Jan
authors.forename: Ming-Chen
authors.initials: MC
authors.lastname: Chou
authors.forename: Yi-Yu
authors.initials: YY
authors.lastname: Ke
authors.forename: Jing
authors.initials: J
authors.lastname: Ma
authors.forename: Ying-Chieh
authors.initials: YC
authors.lastname: Wong
authors.forename: Tsung-Chih
authors.initials: TC
authors.lastname: Hsieh
authors.forename: Yun-Chen
authors.initials: YC
authors.lastname: Tien
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gullen
authors.forename: Chen-Fu
authors.initials: CF
authors.lastname: Lo
authors.forename: Chia-Yi
authors.initials: CY
authors.lastname: Cheng
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Liu
authors.forename: Amit A
authors.initials: AA
authors.lastname: Sadani
authors.forename: Chia-Hua
authors.initials: CH
authors.lastname: Tsai
authors.forename: Hsin-Pang
authors.initials: HP
authors.lastname: Hsieh
authors.forename: Lun K
authors.initials: LK
authors.lastname: Tsou
authors.forename: Kak-Shan
authors.initials: KS
authors.lastname: Shia
mesh_terms: D000818:Animals; D065100:CCR5 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D065100:CCR5 Receptor Antagonists; C527276:CXCR4 protein, human; D023581:HIV Fusion Inhibitors; D019718:Receptors, CXCR4