Discovery of a Lead Compound for Specific Inhibition of Type I Collagen Production in Fibrosis.
Stefanovic B,Michaels HA,Nefzi A
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.