Abstract
Proteasomes are compartmentalized, ATP-dependent, N-terminal nucleophile hydrolases that play essentials roles in intracellular protein turnover. They are present in all 3 kingdoms. Pharmacological inhibition of proteasomes is detrimental to cell viability. Proteasome inhibitor rugs revolutionize the treatment of multiple myeloma. Proteasomes in pathogenic microbes such as Mycobacterium tuberculosis (Mtb), Plasmodium falciparum (Pf), and other parasites and worms have been validated as therapeutic targets. Starting with Mtb proteasome, efforts in developing inhibitors selective for microbial proteasomes have made great progress lately. In this review, we describe the strategies and pharmacophores that have been used in developing proteasome inhibitors with potency and selectivity that spare human proteasomes and highlight the development of clinical proteasome inhibitor candidates for treatment of leishmaniasis and Chagas disease. Finally, we discuss the future challenges and therapeutical potentials of the microbial proteasome inhibitors.
Highlights
Regulated protein degradation is a pivotal process in all cells [1,2]
The ubiquitination cascade is repeated with ubiquitylation of the ubiquitin attached to the protein to produce polyubiquitinated proteins, which are recognized by ubiquitin receptors on the 19S regulatory particle of the proteasome and removed by deubiquitinases (Dubs) prior to unfolding by the ATPases at the base of the 19S
The co-crystal X-ray structure of B6 and the Mtb20SOG showed that the imidazole ring forms 2 additional hydrogen bonds with Gly-47 and Ser-20, and modeling studies showed that the phenylimidazole moiety does not fit in to S1 pocket of either c-20S or i-20S, shedding light on the species selectivity of the phenylimidazole-based Mtb20S inhibitors
Summary
Citation: Zhang H, Lin G (2021) Microbial proteasomes as drug targets. PLoS Pathog 17(12): e1010058. https://doi.org/10.1371/journal. ppat.1010058 Funding: This work was supported by National Institute of Allergy and Infectious Diseases (grants R01AI143714 and R21AI144552 to GL). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist.
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