drug discovery for schistosomiasis hit and lead compounds identified in a library of known drugs by medium-throughput phenotypic screening血吸虫病的药物发现,铅化合物确认在库中已知的药物medium-throughput表型筛选.pdfVIP

Drug Discovery for Schistosomiasis: Hit and Lead Compounds Identified in a Library of Known Drugs by Medium-Throughput Phenotypic Screening 1. 1. 2 2 1 Maha-Hamadien Abdulla , Debbie S. Ruelas , Brian Wolff , June Snedecor , Kee-Chong Lim , Fengyun 1 2 2 1 1 Xu , Adam R. Renslo , Janice Williams , James H. McKerrow , Conor R. Caffrey * 1 Sandler Center for Basic Research in Parasitic Diseases, California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, California, United States of America, 2 Small Molecule Discovery Center, California Institute for Quantitative Biosciences (QB3), University of California, San Francisco, California, United States of America Abstract Background: Praziquantel (PZQ) is the only widely available drug to treat schistosomiasis. Given the potential for drug resistance, it is prudent to search for novel therapeutics. Identification of anti-schistosomal chemicals has traditionally relied on phenotypic (whole organism) screening with adult worms in vitro and/or animal models of disease—tools that limit automation and throughput with modern microtiter plate-formatted compound libraries. Methods: A partially automated, three-component phenotypic screen workflow is presented that utilizes at its apex the schistosomular stage of the parasite adapted to a 96-well plate format with a throughput of 640 compounds per month. Hits that arise are subsequently screened in vitro against adult parasites and finally for efficacy in a murine model of disease. Two GO/NO GO criteria filters in the workflow prioritize hit compounds for tests