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Cyclophilin D as a multiple sclerosis and cardiovascular disease drug target
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"Cyclophilins belong to the immunophilin family and are peptidyl-prolyl isomerases (PPIases) which catalyze the cis-trans interconversion of proline isomers in other proteins, an important step of protein folding. They are widely distributed in all organisms highly conserved throughout evolution. They were originally identified as the biological receptors for immunosuppressants such as Cyclosporine A, highly used to prevent immune response and organ rejection after a transplant. This immunosuppressant effect was determined to be unrelated to the intrinsic isomerase activity. They are known to be involved in pathophysiological process such as inflammation and vascular dysfunction, innate immunity to HIV, hepatitis C infection, neurodegenerative and pathological conditions and tumor biology. In particular, cyclophilin D (CypD), the mitochondrial isoform of the enzyme, is a key regulator of the mitochondrial permeability transition pore. Mitochondrial disfunction has been implicated in multiple sclerosis as well as in cardiovascular disease, suggesting CypD as a potential drug target. Following up on the increased awareness of CypD impact in human health, both pockets (proline and aniline) were screened following a Fragment-Based Drug Discovery approach at Merck KGaA (Darmstadt, Germany) where 58 confirmed fragments hits were obtained, from which only 6 CypD-fragment 3D crystal structures could be obtained.(...)"
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Imunophilins Cyclophilin D Neurodegenerative and Cardiovascular diseases Mitochondrial permeability transition pore (MPTP)