Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
Curr Top Med Chem. 2012;12(22):2546-59. doi: 10.2174/1568026611212220009.
In the past few decades, improved early diagnosis methods, technological developments and an increasing crosstalk between clinicians and researchers has led to the identification of an increasing number of inborn metabolic diseases. In these disorders, missense mutations are the most frequent type of genetic defects, frequently resulting in defective protein folding. A better understanding at the molecular level of protein misfolding and its role in disease has prompted the emergence of therapies based in the use of small molecules that have the ability to correct protein folding defects. Well-known cases are reported for phenylketonuria and Gaucher's disease. Most of these compounds have a specific mechanism of action interacting directly with a particular protein, the so called pharmacological chaperones. Among such small molecules are protein ligands, either natural substrates or synthetic derivatives, cofactors, competitive inhibitors, and agonist/antagonists. In this review we will start by briefly overviewing the mechanisms through which such ligands exert a stabilizing action, and then move on to an extended discussion on therapeutic approaches and use of vitamins and substrates to correct protein misfolding in metabolic disorders. Examples of vitamins that have been successfully prescribed to rescue some cases of inborn errors of metabolism will be presented. In particular, the role of riboflavin supplementation in the treatment of fatty acid β-oxidation disorders will be thoroughly analyzed, focusing on recent reports that shed light on the molecular basis of vitamin responsiveness. Moreover, we will highlight the latest studies that point to a synergistic effect of cofactors and metabolites in the rescue of defective fatty acid β-oxidation enzymes. The synergism of multiple small molecules may underlie a promising general pharmacological strategy for the treatment of metabolic diseases in general.
在过去的几十年中，早期诊断方法的改进、技术的发展以及临床医生和研究人员之间日益增多的交流，导致越来越多的先天性代谢疾病被发现。在这些疾病中，错义突变是最常见的遗传缺陷类型，经常导致蛋白质折叠缺陷。在分子水平上对蛋白质错误折叠及其在疾病中的作用的更好理解，促使基于使用能够纠正蛋白质折叠缺陷的小分子的治疗方法的出现。苯丙酮尿症和戈谢病就是很好的例子。这些化合物中的大多数都具有特定的作用机制，直接与特定的蛋白质相互作用，即所谓的药理学伴侣。这类小分子包括蛋白质配体，无论是天然底物还是合成衍生物、辅助因子、竞争性抑制剂、激动剂/拮抗剂。在这篇综述中，我们将首先简要概述这些配体发挥稳定作用的机制，然后再详细讨论治疗方法以及使用维生素和底物来纠正代谢紊乱中的蛋白质错误折叠。将介绍一些成功用于挽救某些先天性代谢错误的维生素的例子。特别是，将彻底分析核黄素补充治疗脂肪酸β-氧化障碍的作用，重点关注最近的报告，这些报告阐明了维生素反应性的分子基础。此外，我们将强调最新的研究，这些研究表明辅助因子和代谢物在挽救有缺陷的脂肪酸β-氧化酶方面具有协同作用。多种小分子的协同作用可能是治疗代谢疾病的一般有前途的药理学策略的基础。
