Prolyl Isomerases –Old Proteins as New Therapeutic Targets

Prolyl isomerases comprise three main protein families totalling over thirty mammalian genes, and several hundred orthologues across the biological domains, with a very broad spectrum of physiological functions and disease implications. Potent small molecule inhibitors exist for members of the three main mammalian families (cyclophilins, FKBPs and parvulins),. but, until recently, these proteins have not received the attention of the pharmaceutical industry that they merit. Perceptions and experimental difficulties of lead finding and functional screens made the whole class unattractive for drug discovery. Over the last ten years however, interest in prolyl isomerase-directed drug discovery has started to increase. This article discusses the history of prolyl isomerases, their physiological functions in health and disease, the therapeutic potential of inhibitors and drug discovery challenges.