Leidenheimer Nancy J
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center - Shreveport, Shreveport, LA, USA.
Handb Exp Pharmacol. 2018;245:135-153. doi: 10.1007/164_2017_68.
Pharmacological chaperones (PCs) are small molecules that bind to nascent protein targets to facilitate their biogenesis. The ability of PCs to assist in the folding and subsequent forward trafficking of disease-causative protein misfolding mutants has opened new avenues for the treatment of conformational diseases such as cystic fibrosis and lysosomal storage disorders. In this chapter, an overview of the use of PCs for the treatment of conformational disorders is provided. Beyond the therapeutic application of PCs for the treatment of these disorders, pharmacological chaperoning of wild-type integral membrane proteins is discussed. Central to this discussion is the notion that the endoplasmic reticulum is a reservoir of viable but inefficiently processed wild-type protein folding intermediates whose biogenesis can be facilitated by PCs to increase functional pools. To date, the potential therapeutic use of PCs to enhance the biogenesis of wild-type proteins has received little attention. Here the rationale for the development of PCs that target WT proteins is discussed. Also considered is the likelihood that some commonly used therapeutic agents may exert unrecognized pharmacological chaperoning activity on wild-type targets in patient populations.
药理伴侣（PCs）是一类小分子，它们与新生的蛋白质靶点结合，以促进其生物合成。PCs协助致病蛋白错误折叠突变体折叠并随后进行正向运输的能力，为治疗诸如囊性纤维化和溶酶体贮积症等构象疾病开辟了新途径。在本章中，将概述PCs在治疗构象疾病中的应用。除了PCs在治疗这些疾病中的治疗应用外，还将讨论野生型整合膜蛋白的药理伴侣作用。本次讨论的核心观点是，内质网是可行但加工效率低下的野生型蛋白质折叠中间体的储存库，PCs可以促进这些中间体的生物合成，以增加功能库。迄今为止，PCs增强野生型蛋白质生物合成的潜在治疗用途很少受到关注。本文将讨论开发靶向野生型蛋白质的PCs的基本原理。同时还考虑了一些常用治疗药物可能对患者群体中的野生型靶点发挥未被认识的药理伴侣活性的可能性。
