Institute of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, 06099, Halle (Saale), Germany.
Max Planck Institute for Biophysical Chemistry, 37077, Göttingen, Germany.
Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202201597. doi: 10.1002/anie.202201597. Epub 2022 Aug 19.
Cyclophilins, enzymes with peptidyl-prolyl cis/trans isomerase activity, are relevant to a large variety of biological processes. The most abundant member of this enzyme family, cyclophilin A, is the cellular receptor of the immunosuppressive drug cyclosporine A (CsA). As a consequence of the pathophysiological role of cyclophilins, particularly in viral infections, there is a broad interest in cyclophilin inhibition devoid of immunosuppressive activity. This Review first gives an introduction into the physiological and pathophysiological roles of cyclophilins. The presentation of non-immunosuppressive cyclophilin inhibitors will commence with drugs based on chemical modifications of CsA. The naturally occurring macrocyclic sanglifehrins have become other lead structures for cyclophilin-inhibiting drugs. Finally, de novo designed compounds, whose structures are not derived from or inspired by natural products, will be presented. Relevant synthetic concepts will be discussed, but the focus will also be on biochemical studies, structure-activity relationships, and clinical studies.
亲环素是一类具有肽基脯氨酰顺反异构酶活性的酶，与多种生物学过程相关。该酶家族中丰度最高的成员亲环素 A 是免疫抑制剂环孢素 A（CsA）的细胞受体。亲环素在生理和病理生理学方面发挥着重要作用，特别是在病毒感染方面，因此人们广泛关注无免疫抑制活性的亲环素抑制作用。本综述首先介绍了亲环素的生理和病理生理学作用。非免疫抑制性亲环素抑制剂的介绍将从基于 CsA 化学修饰的药物开始。天然存在的大环 sanglifehrin 已成为亲环素抑制药物的另一种主要结构。最后，将介绍从头设计的化合物，其结构不是来源于或受天然产物启发。将讨论相关的合成概念，但重点也将放在生化研究、构效关系和临床研究上。
