2. Academic Validation
  3. Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity

Development of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity

  • J Med Chem. 2017 Aug 10;60(15):6721-6732. doi: 10.1021/acs.jmedchem.7b00671.
Gregory M LaMonte 1,  Jehad Almaliti 2 3,  Betsaida Bibo-Verdugo 4,  Lena Keller 2,  Bing Yu Zou 1,  Jennifer Yang 1,  Yevgeniya Antonova-Koch 1,  Pamela Orjuela-Sanchez 1,  Colleen A Boyle 1,  Edgar Vigil 1,  Lawrence Wang 1,  Gregory M Goldgof 1,  Lena Gerwick 4,  Anthony J O'Donoghue 4,  Elizabeth A Winzeler 1,  William H Gerwick 4 2,  Sabine Ottilie 1
Affiliations

Affiliations

  • 1 Department of Pediatrics, School of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
  • 2 Scripps Institution of Oceanography, University of California, San Diego , La Jolla, California 92093, United States.
  • 3 Department of Pharmaceutical Sciences, Faculty of Pharmacy, The University of Jordan , Amman 11942, Jordan.
  • 4 Skaggs School of Pharmacy and Pharmaceutical Sciences, Faculty of Pharmacy, and School of Medicine, University of California, San Diego , La Jolla, California 92093, United States.
PMID: 28696697 DOI: 10.1021/acs.jmedchem.7b00671
Abstract

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 β5 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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