Protein misfolding induced by missense mutations is the source of hundreds of conformational diseases. The cell quality control may eliminate nascent misfolded proteins, such as enzymes, and a pathological loss-of-function may result from their early degradation. Since the proof of concept in the 2000s, the bioinspired pharmacological chaperone therapy became a relevant low-molecular-weight compound strategy against conformational diseases. The first-generation pharmacological chaperones were competitive inhibitors of mutant enzymes. Counterintuitively, in binding to the active site, these inhibitors stabilize the proper folding of the mutated protein and partially rescue its cellular function. The main limitation of the first-generation pharmacological chaperones lies in the balance between enzyme activity enhancement and inhibition. Recent research efforts were directed towards the development of promising second-generation pharmacological chaperones. These non-inhibitory ligands, targeting previously unknown binding pockets, limit the risk of adverse enzymatic inhibition. Their pharmacophore identification is however challenging and likely requires a massive screening-based approach. This review focuses on second-generation chaperones designed to restore the cellular activity of misfolded enzymes. It intends to highlight, for a selected set of rare inherited metabolic disorders, the strategies implemented to identify and develop these pharmacologically relevant small organic molecules as potential drug candidates.

中文翻译：

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第二代药理学伴侣：超越抑制剂

由错义突变引起的蛋白质错误折叠是数百种构象疾病的根源。细胞质量控制可以消除新生的错误折叠蛋白质，例如酶，并且它们的早期降解可能导致病理性功能丧失。自 2000 年代概念验证以来，仿生药理学伴侣疗法成为对抗构象疾病的相关低分子量化合物策略。第一代药理学伴侣是突变酶的竞争性抑制剂。与直觉相反，在与活性位点结合时，这些抑制剂稳定了突变蛋白质的正确折叠并部分挽救了其细胞功能。第一代药理分子伴侣的主要局限在于酶活性增强和抑制之间的平衡。最近的研究工作旨在开发有前景的第二代药理学伴侣。这些非抑制性配体靶向以前未知的结合口袋，限制了不利酶抑制的风险。然而，它们的药效团识别具有挑战性，可能需要大量基于筛选的方法。本综述重点介绍旨在恢复错误折叠酶的细胞活性的第二代分子伴侣。它打算强调，对于一组选定的罕见遗传代谢紊乱，实施策略以识别和开发这些药理学相关的小有机分子作为潜在的候选药物。针对以前未知的结合口袋，限制不利酶抑制的风险。然而，它们的药效团识别具有挑战性，可能需要大量基于筛选的方法。本综述重点介绍旨在恢复错误折叠酶的细胞活性的第二代分子伴侣。它打算强调，对于一组选定的罕见遗传代谢紊乱，实施策略以识别和开发这些药理学相关的小有机分子作为潜在的候选药物。靶向先前未知的结合口袋，限制不利酶抑制的风险。然而，它们的药效团识别具有挑战性，可能需要大量基于筛选的方法。本综述重点介绍旨在恢复错误折叠酶的细胞活性的第二代分子伴侣。它打算强调，对于一组选定的罕见遗传代谢紊乱，实施策略以识别和开发这些药理学相关的小有机分子作为潜在的候选药物。