Papp E, Csermely P
Department of Medical Chemistry, Semmelweis University, Budapest, Hungary.
Handb Exp Pharmacol. 2006(172):405-16. doi: 10.1007/3-540-29717-0_16.
An increasing number of studies indicate that low-molecular-weight compounds can help correct conformational diseases by inhibiting the aggregation or enable the mutant proteins to escape the quality control systems, and thus their function can be rescued. The small molecules were named chemical chaperones and it is thought that they nonselectively stabilize the mutant proteins and facilitate their folding. Chemical chaperones are usually osmotically active, such as DMSO, glycerol, or deuterated water, but other compounds, such as 4-phenylbutiric acid, are also members of the chemical chaperone group. More recently, compounds such as receptor ligands or enzyme inhibitors, which selectively recognize the mutant proteins, were also found to rescue conformational mutants and were termed pharmacological chaperones. An increasing amount of evidence suggests that the action of pharmacological chaperones could be generalized to a large number of misfolded proteins, representing new therapeutic possibilities for the treatment of conformational diseases. A new and exciting strategy has recently been developed, leading to the new chemical group called folding agonist. These small molecules are designed to bind proteins and thus restore their native conformation.
越来越多的研究表明，低分子量化合物可通过抑制聚集或使突变蛋白逃避质量控制系统来帮助纠正构象疾病，从而挽救其功能。这些小分子被称为化学伴侣，人们认为它们可非选择性地稳定突变蛋白并促进其折叠。化学伴侣通常具有渗透活性，如二甲基亚砜、甘油或重水，但其他化合物，如4-苯基丁酸，也是化学伴侣组的成员。最近，还发现了诸如受体配体或酶抑制剂等能选择性识别突变蛋白的化合物，它们可挽救构象突变体，被称为药理伴侣。越来越多的证据表明，药理伴侣的作用可推广到大量错误折叠的蛋白，为构象疾病的治疗带来了新的治疗可能性。最近开发了一种新的、令人兴奋的策略，产生了名为折叠激动剂的新化学基团。这些小分子被设计用于结合蛋白，从而恢复其天然构象。
