Reinecke Bethany A, Kang Guifeng, Zheng Yi, Obeng Samuel, Zhang Huijun, Selley Dana E, An Jing, Zhang Yan
Department of Medicinal Chemistry , Virginia Commonwealth University , 800 East Leigh Street , Richmond , VA 23298 , USA . Email:
Department of Medicine , Division of Infectious Diseases , School of Medicine , University of California San Diego , 9500 Gilman Drive, Stein Clinical Research Building, Suite 410 , La Jolla , CA 92093 , USA.
RSC Med Chem. 2019 Dec 19;11(1):125-131. doi: 10.1039/c9md00433e. eCollection 2020 Jan 1.
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.
阿片类药物滥用和艾滋病毒/艾滋病已被定义为协同流行疾病。阿片类药物可通过上调艾滋病毒共受体CXCR4的表达来加速免疫系统中的艾滋病毒复制。有人提出了几种假说，作为阿片类药物通过激活μ阿片受体（MOR）来调节CXCR4的机制。一种假说是MOR与CXCR4假定的异源二聚化，作为一种相互作用及随后加剧艾滋病毒复制的机制。二价化学探针可能是表征蛋白质-蛋白质相互作用并调节与此类相互作用相关功能的强大分子工具。在此，我们报告一种新型二价探针的设计与合成，以探索假定的MOR-CXCR4二聚化及其在增强艾滋病毒进展中的潜在药理学作用。所开发的二价探针设计为通过一个间隔基连接的两个不同药效基团。一个药效基团（纳曲酮）将与MOR相互作用，另一个（IT1t）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包括18-22步，产率尚可。初步生物学评估表明，二价探针在各自的受体上均保留了结合亲和力和功能活性，支持最初的分子设计。
