drug discovery for duchenne muscular dystrophy via utrophin promoter activation screening杜氏肌萎缩症药物发现为通过拉子激活筛选.pdfVIP

Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening 1¤a 2 1¤b 2¤c 2 Catherine Moorwood , Olga Lozynska , Neha Suri , Andrew D. Napper , Scott L. Diamond , Tejvir S. Khurana1* 1 Department of Physiology and Pennsylvania Muscle Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America, 2 Penn Center for Molecular Discovery, Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America Abstract Background: Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings: We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits