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Targeting the ERAD Pathway via Inhibition of Signal Peptide Peptidase for Antiparasitic Therapeutic Design

Harbut, Michael B. and Patel, Bhumit A. and Yeung, Bryan King Sing and Mcnamara, Case and Golde, Todd E. and Winzeler, Elizabeth and Diagana, Thierry Tidiane and Greenbaum, Doron C. (2012) Targeting the ERAD Pathway via Inhibition of Signal Peptide Peptidase for Antiparasitic Therapeutic Design. Proceedings of the National Academy of Sciences USA, 109 (52). pp. 21486-21491. ISSN 0027-8424

Abstract

Early secretory and endoplasmic reticulum (ER)-localized proteins that are terminally misfolded or misassembled are degraded by a ubiquitin- and proteasome-mediated process known as ER-associated degradation (ERAD). Protozoan pathogens, including the causative agents of malaria, toxoplasmosis, and leishmaniasis, contain a minimal ERAD network relative to higher eukaryotic cells. Herein, we exploit this fact to show that the malaria parasite Plasmodium falciparum is highly sensitized to the inhibition of components of this protein quality control system. Using a variety of approaches, including activity-based protein profiling, mammalian cell- and yeast-based assays, and resistance selection, we show small molecule inhibitors of a protease component of malarial ERAD, PfSPP, simultaneously disrupt the protein’s ability to facilitate degradation of unstable proteins and inhibit its proteolytic function, resulting in lethality for the parasite. Collectively, these data validate ER quality control as a novel vulnerability for the parasite and specifically, confirm the suitability of PfSPP as an antimalarial target.

Item Type: Article
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/8186

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