Biological and mutational analyses of CXCR4-antagonist interactions and design of new antagonistic analogs

Biosci Rep. 2023 Dec 22;43(12):BSR20230981. doi: 10.1042/BSR20230981.ABSTRACTThe chemokine receptor CXCR4 has become an attractive therapeutic target for HIV-1 infection, hematopoietic stem cell mobilization, and cancer metastasis. A wide variety of synthetic antagonists of CXCR4 have been developed and studied for a growing list of clinical applications. To compare the biological effects of different antagonists on CXCR4 functions and their common and/or distinctive molecular interactions with the receptor, we conducted head-to-head comparative cell-based biological and mutational analyses of the interactions with CXCR4 of eleven reported antagonists, including HC4319, DV3, DV1, DV1 dimer, V1, vMIP-II, CVX15, LY2510924, IT1t, AMD3100, and AMD11070 that were representative of different structural classes of D-peptides, L-peptide, natural chemokine, cyclic peptides, and small molecules. The results were rationalized by molecular modeling of CXCR4-antagonist interactions from which the common as well as different receptor binding sites of these antagonists were derived, revealing a number of important residues such as W94, D97, H113, D171, D262, and E288, mostly of negative charge. To further examine this finding, we designed and synthesized new antagonistic analogs by adding positively charged residues Arg to a D-peptide template to enhance the postulated charge-charge interactions. The newly designed analogs displayed significantly increased binding to CXCR4, which supports t...

Source: Bioscience Reports - December 22, 2023 Category: Biomedical Science Authors: Qian Meng Ruohan Zhu Yujia Mao Siyu Zhu Yi Wu Lina S M Huang Aaron Ciechanover Jing An Yan Xu Ziwei Huang Source Type: research