Development of piperazine-based hydroxamic acid inhibitors against falcilysin,an essential malarial protease |
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| Authors: | Jeffrey P Chance Hannah Fejzic Obiel Hernandez Eva S Istvan Armann Andaya Nikolay Maslov Ruby Aispuro Teodulo Crisanto Huyen Nguyen Brian Vidal Whitney Serrano Bradley Kuwahara Corey Pugne Andanado Daniel E Goldberg Jeremy P Mallari |
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| Institution: | 1. Department of Chemistry and Biochemistry, California State University, San Bernardino, USA;2. Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, Saint Louis, USA;3. Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, USA;4. Campus Mass Spectrometry Facilities, University of California, Davis, USA |
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| Abstract: | The human parasite Plasmodium falciparum kills an estimated 445,000 people a year, with the most fatalities occurring in African children. Previous studies identified falcilysin (FLN) as a malarial metalloprotease essential for parasite development in the human host. Despite its essentiality, the biological roles of this protease are not well understood. Here we describe the optimization of a piperazine-based hydroxamic acid scaffold to develop the first reported inhibitors of FLN. Inhibitors were tested against cultured parasites, and parasiticidal activity correlated with potency against FLN. This suggests these compounds kill P. falciparum by blocking FLN, and that FLN is a druggable target. These compounds represent an important step towards validating FLN as a therapeutic target and towards the development of chemical tools to investigate the function of this protease. |
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| Keywords: | RBC Red blood cell IPTG FLN Falcilysin PMSF Phenylmethylsulfonyl fluoride TEA Triethylamine ER Endoplasmic reticulum DMAP 4-Dimethylaminopyridine Falcilysin Malaria Protease inhibitors Metalloprotease Hydroxamic acid |
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