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Development of piperazine-based hydroxamic acid inhibitors against falcilysin, an essential malarial protease.

Authors
  • Chance, Jeffrey P1
  • Fejzic, Hannah1
  • Hernandez, Obiel1
  • Istvan, Eva S2
  • Andaya, Armann3
  • Maslov, Nikolay1
  • Aispuro, Ruby1
  • Crisanto, Teodulo1
  • Nguyen, Huyen1
  • Vidal, Brian1
  • Serrano, Whitney1
  • Kuwahara, Bradley1
  • Pugne Andanado, Corey1
  • Goldberg, Daniel E2
  • Mallari, Jeremy P4
  • 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; Department of Molecular Microbiology, Washington University School of Medicine, Saint Louis, USA.
  • 3 Campus Mass Spectrometry Facilities, University of California, Davis, USA.
  • 4 Department of Chemistry and Biochemistry, California State University, San Bernardino, USA. Electronic address: [email protected]
Type
Published Article
Journal
Bioorganic & medicinal chemistry letters
Publication Date
Apr 19, 2018
Identifiers
DOI: 10.1016/j.bmcl.2018.04.010
PMID: 29691139
Source
Medline
Keywords
License
Unknown

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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