Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 60, Issue 15, Pages 6721-6732Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b00671
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Funding
- A.P. Giannini Postdoctoral Fellowship
- Bill and Melinda Gates Foundation
- Grand Challenge in Global Health Exploration Grants [OPP1086217, OPP1141300]
- UC San Diego Medical Scientist Training Program [T32 GM007198-40]
- DoD National Defense Science and Engineering Fellowship Program
- Deutsche Forschungsgemeinschaft [KE 2172/3-1]
- Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego
- NIH [5R01A1090141, R01A1103058, GM107550, AI127505]
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Naturally derived chemical compounds are the foundation of much of our pharmacopeia, especially in antiproliferative and anti-infective drug classes. Here, we report that a naturally derived molecule called carmaphycin B is a potent inhibitor against both the asexual and sexual blood stages of malaria infection. Using a combination of in silico molecular docking and in vitro directed evolution in a well characterized drug-sensitive yeast model, we determined that these compounds target the beta 5 subunit of the proteasome. These studies were validated using in vitro inhibition assays with proteasomes isolated from Plasmodium falciparum. As carmaphycin B is toxic to mammalian cells, we synthesized a series of chemical analogs that reduce host cell toxicity while maintaining blood-stage and gametocytocidal antimalarial activity and proteasome inhibition. This study describes a promising new class of antimalarial compound based on the carmaphycin B scaffold, as well as several chemical structural features that serve to enhance antimalarial specificity.
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