University of California, San Diego, Skaggs School of Pharmacy andPharmaceutical Sciences, La Jolla, CA 92093, USA.
Expert Opin Drug Discov. 2010 Nov;5(11):1109-22. doi: 10.1517/17460441.2010.525633.
Chemokine receptors are most noted for their role in cell migration. However, inappropriate utilization or regulation of these receptors is implicated in many inflammatory diseases, cancer and HIV, making them important drug targets.
Allostery, oligomerization and ligand bias are presented as they pertain to chemokine receptors and their associated pathologies.Specific examples of each are described from the recent literature and their implications are discussed in terms of drug discovery efforts targeting chemokine receptors.
Insight into the expanding view of the multitude of pharmacological variables that need to be considered or that may be exploited in chemokine receptor drug discovery.
Since 2007, two drugs targeting chemokine receptors have been approved by the FDA, Maraviroc for preventing HIV infection and Mozobil™ for hematopoietic stem cell mobilization. While these successes permit optimism for chemokine receptors as drug targets, only recently has the complexity of this system begun to be appreciated. The concepts of allosteric inhibitors, biased ligands and functional selectivity raise the possibility that drugs with precisely-defined properties can be developed. Other complexities such as receptor oligomerization and tissue-specific functional states of receptors also offer opportunities for increased target and response specificity, although it will be more challenging to translate these ideas into approved therapeutics compared to traditional approaches.
趋化因子受体最显著的特点是它们在细胞迁移中的作用。然而，这些受体的不适当利用或调节与许多炎症性疾病、癌症和 HIV 有关，使它们成为重要的药物靶点。
变构、寡聚化和配体偏倚是趋化因子受体及其相关病理的表现。从最近的文献中描述了每个的具体例子，并讨论了它们在针对趋化因子受体的药物发现努力中的意义。
深入了解趋化因子受体药物发现中需要考虑或可能利用的多种药理学变量的扩展观点。
自 2007 年以来，两种针对趋化因子受体的药物已获得 FDA 批准，Maraviroc 用于预防 HIV 感染，Mozobil™用于造血干细胞动员。虽然这些成功使人们对趋化因子受体作为药物靶点持乐观态度，但直到最近，人们才开始意识到该系统的复杂性。变构抑制剂、偏向配体和功能选择性的概念提出了这样一种可能性，即可以开发具有精确定义特性的药物。其他复杂性，如受体寡聚化和受体的组织特异性功能状态，也为提高靶标和反应特异性提供了机会，尽管与传统方法相比，将这些想法转化为已批准的治疗方法将更加具有挑战性。
