Design, synthesis, and biological characterization of a new class of symmetrical polyamine-based small molecule CXCR4 antagonists.

Abstract

CXCR4, a well-studied coreceptor of human immunodeficiency virus type 1 (HIV-1) entry, recognizes its cognate ligand SDF-1α (also named CXCL12) which plays many important roles, including regulating immune cells, controlling hematopoietic stem cells, and directing cancer cells migration. These pleiotropic roles make CXCR4 an attractive target to mitigate human disorders. Here a new class of symmetrical polyamines was designed and synthesized as potential small molecule CXCR4 antagonists. Among them, a representative compound 21 (namely HF50731) showed strong CXCR4 binding affinity (mean IC50 = 19.8 nM) in the CXCR4 competitive binding assay. Furthermore, compound 21 significantly inhibited SDF-1α-induced calcium mobilization and cell migration, and blocked HIV-1 infection via antagonizing CXCR4 coreceptor function. The structure-activity relationship analysis, site-directed mutagenesis, and molecular docking were conducted to further elucidate the binding mode of compound 21, suggesting that compound 21 could primarily occupy the minor subpocket of CXCR4 and partially bind in the major subpocket by interacting with residues W94, D97, D171, and E288. Our studies provide not only new insights for the fragment-based design of small molecule CXCR4 antagonists for clinical applications, but also a new and effective molecular probe for CXCR4-targeting biological studies.

• Authors: Xiong Fang, Qian Meng, Huijun Zhang, Boqiang Liang, Siyu Zhu, Juan Wang, Chaozai Zhang, Lina S Huang, Xingquan Zhang, Robert T Schooley, Jing An, Yan Xu, Ziwei Huang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 200 Pg. 112410 (Aug 15 2020) ISSN: 1768-3254 [Electronic] France
• PMID: 32492596 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Chemical References

• CXCL12 protein, human
• CXCR4 protein, human
• Chemokine CXCL12
• Peptide Fragments
• Polyamines
• Receptors, CXCR4

Topics

• Binding Sites
• Binding, Competitive
• Cell Line
• Chemokine CXCL12
• Drug Design
• HIV Infections (prevention & control)
• Humans
• Inhibitory Concentration 50
• Molecular Docking Simulation
• Mutagenesis, Site-Directed
• Peptide Fragments (chemistry)
• Polyamines (chemical synthesis, pharmacology)
• Receptors, CXCR4 (antagonists & inhibitors)