Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer,RSC Medicinal Chemistry

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Design and synthesis of a bivalent probe targeting the putative mu opioid receptor and chemokine receptor CXCR4 heterodimer
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2019/12/19 , DOI: 10.1039/c9md00433e
Bethany A Reinecke ₁ , Guifeng Kang ₁ , Yi Zheng ₁ , Samuel Obeng ₁ , Huijun Zhang ₂ , Dana E Selley ₃ , Jing An ₂ , Yan Zhang ₁

Affiliation

Opioid abuse and HIV/AIDS have been defined as synergistic epidemics. Opioids can accelerate HIV replication in the immune system by up-regulating the expression of HIV co-receptor CXCR4. Several hypotheses have been suggested as the mechanism of CXCR4 modulation by opioids through their activation on the mu opioid receptor (MOR). One hypothesis is the putative heterodimerization of the MOR and CXCR4 as a mechanism of cross-talk and subsequent exacerbation of HIV replication. Bivalent chemical probes can be powerful molecular tools to characterize protein–protein interactions, and modulate the function related to such interactions. Herein we report the design and synthesis of a novel bivalent probe to explore the putative MOR–CXCR4 dimerization and its potential pharmacological role in enhancing HIV progression. The developed bivalent probe was designed with two distinct pharmacophores linked through a spacer. One pharmacophore (naltrexone) will interact with the MOR and the other (IT1t) with the CXCR4. The overall synthetic routes to prepare the bivalent probe and its corresponding monovalent controls were comprised of 18–22 steps with acceptable yields. Preliminary biological evaluation showed that the bivalent probe preserved binding affinity and functional activity at both respective receptors, supporting the initial molecular design.

中文翻译：

设计和合成针对假定的 mu 阿片受体和趋化因子受体 CXCR4 异二聚体的二价探针

阿片类药物滥用和艾滋病毒/艾滋病被定义为协同流行病。阿片类药物可以通过上调 HIV 辅助受体 CXCR4 的表达来加速 HIV 在免疫系统中的复制。一些假设被认为是阿片类药物通过激活 mu 阿片受体 (MOR) 来调节 CXCR4 的机制。一种假设是 MOR 和 CXCR4 的异二聚化是一种相互干扰和随后加剧 HIV 复制的机制。二价化学探针可以成为表征蛋白质-蛋白质相互作用并调节与此类相互作用相关的功能的强大分子工具。在此，我们报告了一种新型二价探针的设计和合成，以探索假定的 MOR-CXCR4 二聚化及其在促进 HIV 进展中的潜在药理学作用。开发的二价探针设计有通过间隔基连接的两个不同的药效团。一种药效团（纳曲酮）将与 MOR 相互作用，另一种药效团（IT1t）将与 CXCR4 相互作用。制备二价探针及其相应单价对照的总体合成路线由 18-22 个步骤组成，且收率可接受。初步生物学评估表明，二价探针保留了两个各自受体的结合亲和力和功能活性，支持了最初的分子设计。

更新日期：2020-02-13

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