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

TitleDevelopment of a Potent Inhibitor of the Plasmodium Proteasome with Reduced Mammalian Toxicity
Publication TypeJournal Article
Year of Publication2017
AuthorsLaMonte G.M, Almaliti J., Bibo-Verdugo B., Keller L., Zou B.Y, Yang J., Antonova-Koch Y., Orjuela-Sanchez P., Boyle C.A, Vigil E., Wang L., Goldgof G.M, Gerwick L, O'Donoghue A.J, Winzeler E.A, Gerwick WH, Ottilie S.
JournalJournal of Medicinal Chemistry
Volume60
Pagination6721-6732
Date Published2017/08
Type of ArticleArticle
ISBN Number0022-2623
Accession NumberWOS:000407656700017
Keywords20s proteasome; carfilzomib; design; discovery; in-vitro; malaria; mechanism; natural-products; Pharmacology & Pharmacy; saccharomyces-cerevisiae; target
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 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.

DOI10.1021/acs.jmedchem.7b00671
Short TitleJ. Med. Chem.
Student Publication: 
No
Research Topics: 
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