Faculty of Science and Engineering, School of Healthcare Science, Manchester Metropolitan University, Manchester, United Kingdom.
Hospital de la Santa Creu I Sant Pau, IIB Sant Pau, Barcelona, Spain.
Front Immunol. 2018 May 28;9:1089. doi: 10.3389/fimmu.2018.01089. eCollection 2018.
Circulating C-reactive protein (CRP) is a key acute-phase protein and one of the main clinical biomarkers for inflammation and infection. CRP is an important upstream mediator of inflammation and is associated with the onset of a number of important disease states including cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease. This pentraxin exerts pro-inflammatory properties dissociation of the pentamer (pCRP) to a monomeric form (mCRP). This dissociation is induced by binding of pCRP to cell surface phosphocholine residues exposed by the action of phospholipase A (PLA). Given the association of CRP with the onset of a range of serious disease states this CRP dissociation process is a tempting drug target for the development of novel small-molecule therapeutics. This review will discuss potential targets for chemotherapeutic intervention elucidated during studies of CRP-mediated inflammation and provide an up-to-date summary of the development of small molecules, not only targeted directly at inhibiting conversion of pCRP to mCRP, but also those developed for activity against PLA, given the key role of this enzyme in the activation of CRP.
循环 C 反应蛋白 (CRP) 是一种关键的急性期蛋白，也是炎症和感染的主要临床生物标志物之一。CRP 是炎症的重要上游介质，与多种重要疾病状态的发生有关，包括心血管疾病和神经退行性疾病，如阿尔茨海默病。这种五聚蛋白具有促炎特性，其单体形式（mCRP）是通过五聚体（pCRP）的解离产生的。这种解离是由 pCRP 与细胞膜表面磷酸胆碱残基的结合诱导的，这些磷酸胆碱残基是由磷脂酶 A (PLA) 的作用暴露的。鉴于 CRP 与一系列严重疾病状态的发生有关，因此 CRP 解离过程是开发新型小分子治疗药物的一个有吸引力的药物靶点。本文综述了 CRP 介导的炎症研究中阐明的潜在化学治疗干预靶点，并对小分子的开发进行了最新总结，不仅针对直接抑制 pCRP 转化为 mCRP 的靶点，还针对 PLA 的靶点，因为该酶在 CRP 的激活中起着关键作用。
