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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Novel compounds containing multiple guanide groups that bind the HIV coreceptor CXCR4.
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Novel compounds containing multiple guanide groups that bind the HIV coreceptor CXCR4.

机译：包含多个结合HIV共受体CXCR4的胍基的新型化合物。

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摘要

The G-protein-coupled receptor CXCR4 acts as a coreceptor for human immunodeficiency virus type 1 (HIV-1) infection, as well as being involved in signaling cell migration and proliferation. Compounds that block CXCR4 interactions have potential uses as HIV entry inhibitors to complement drugs such as maraviroc that block the alternate coreceptor CCR5 or in cancer therapy. The peptide T140, which contains five arginine residues, is the most potent antagonist of CXCR4 developed to date. In a search for nonpeptide CXCR4 ligands that could inhibit HIV entry, three series of compounds were synthesized from 12 linear and branched polyamines with 2, 3, 4, 6, or 8 amino groups, which were substituted to produce the corresponding guanidines, biguanides, or phenylguanides. The resulting compounds were tested for their ability to compete with T140 for binding to the human CXCR4 receptor expressed on mammalian cells. The most effective compounds bound CXCR4 with a 50% inhibitory concentration of 200 nM, and all of the compounds had very low cytotoxicity. Two series of compounds were then tested for their ability to inhibit the infection of TZM-bl cells with X4 and R5 strains of HIV-1. Spermine phenylguanide and spermidine phenylguanide inhibited infection by X4 strains, but not by R5 strains, at low micromolar concentrations. These results support further investigation and development of these compounds as HIV entry inhibitors.
机译：G蛋白偶联受体CXCR4充当1型人类免疫缺陷病毒（HIV-1）感染的共受体，并参与细胞迁移和增殖的信号传递。阻断CXCR4相互作用的化合物具有潜在的用途，可以作为HIV进入抑制剂来补充诸如maraviroc之类的药物，后者可以替代替代的共受体CCR5或用于癌症治疗。含有五个精氨酸残基的肽T140是迄今为止开发的最有效的CXCR4拮抗剂。为了寻找可抑制HIV进入的非肽CXCR4配体，由12个具有2,3、4、6、8个氨基的直链和支链多胺合成了三组化合物，这些胺被取代后生成相应的胍，双胍，或苯基胍。测试所得化合物与T140竞争结合在哺乳动物细胞上表达的人CXCR4受体的能力。最有效的化合物以200 nM的50％抑制浓度结合CXCR4，所有化合物的细胞毒性都非常低。然后测试两个系列的化合物抑制HIV-1的X4和R5菌株感染TZM-b1细胞的能力。在低微摩尔浓度下，精胺苯胍和亚精胺苯胍抑制X4菌株的感染，但不抑制R5菌株的感染。这些结果支持进一步研究和开发这些化合物作为HIV进入抑制剂。

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