Stefanovic Branko, Michaels Heather A, Nefzi Adel
Florida State University, 1115 West Call Street, Tallahassee, Florida 32306, United States.
Indian River State College, Fort Pierce, Florida 34981, United States.
ACS Med Chem Lett. 2021 Feb 24;12(3):477-484. doi: 10.1021/acsmedchemlett.1c00006. eCollection 2021 Mar 11.
Fibrosis is a major medical problem caused by excessive synthesis of the extracellular matrix, composed predominantly of type I collagen, in various tissues. There are no approved antifibrotic drugs, and the major obstacle in finding clinically relevant compounds is the lack of specificity of current experimental drugs for type I collagen. Here we describe the discovery of a lead compound that specifically inhibited secretion of type I collagen by fibroblasts in culture at IC = 4.5 μM. The inhibition was specific for type I collagen, because secretion of fibronectin was not affected. In vitro, the compound inhibited binding of LARP6, the master regulator of translation of type I collagen mRNAs, to the 5' stem-loop sequence element which regulates their translation. Because binding of LARP6 to collagen mRNAs is crucial for the development of fibrosis, this inhibitor represents a promising lead for optimization into specific antifibrotic drugs.
纤维化是一个主要的医学问题，它由细胞外基质过度合成引起，细胞外基质主要由I型胶原蛋白组成，存在于各种组织中。目前尚无获批的抗纤维化药物，而寻找具有临床相关性化合物的主要障碍是当前实验药物对I型胶原蛋白缺乏特异性。在此，我们描述了一种先导化合物的发现，该化合物在IC = 4.5 μM时可特异性抑制培养的成纤维细胞分泌I型胶原蛋白。这种抑制作用对I型胶原蛋白具有特异性，因为纤连蛋白的分泌不受影响。在体外，该化合物抑制I型胶原蛋白mRNA翻译的主要调节因子LARP6与调控其翻译的5'茎环序列元件的结合。由于LARP6与胶原蛋白mRNA的结合对于纤维化的发展至关重要，因此这种抑制剂有望被优化为特异性抗纤维化药物。
