Journal
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
Volume 32, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2020.127683
Keywords
Malaria; Protease inhibitors; Metalloprotease inhibitors; Parasitology; Computational binding model
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Funding
- CSUSB Office of Research
- California State University CSUPERB New Investigator Grant program
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This study focused on investigating the function of the protease FLN in the protozoan parasite Plasmodium falciparum, which causes severe human malaria. The development of inhibitors targeting FLN showed significant improvements in potency against purified FLN and cultured P. falciparum, with computational studies predicting a binding model consistent with biochemical data.
The protozoan parasite Plasmodium falciparum causes the most severe form of human malaria and is estimated to kill 400,000 people a year. The parasite infects and replicates in host red blood cells (RBCs), where it expresses an array of proteases to carry out multiple essential processes. We are investigating the function of falcilysin (FLN), a protease known to be required for parasite development in the RBC. We previously developed a piperazine-based hydroxamic acid scaffold to generate the first inhibitors of FLN, and the current study reports the optimization of the lead compound from that series. A range of substituents were tested at the N1 and N4 positions of the piperazine core, and inhibitors with significantly improved potency against purified FLN and cultured P. falciparum were identified. Computational studies were also performed to understand the mode of binding for these compounds, and predicted a binding model consistent with the biochemical data and the distinctive SAR observed at both the N1 and N4 positions.
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