Microbial proteasomes as drug targets

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.

Discovery of Highly Selective Inhibitors of the Human Constitutive Proteasome β5c Chymotryptic Subunit

“…Proteasome inhibitor drugs started the new era of treatment of multiple myeloma and have now been approved for additional diseases such as mantle cell lymphoma. Recently, pathogen proteasome-selective inhibitors that spare human proteasomes are being pursued for infectious diseases. , Subunit-specific proteasome inhibitors have been constantly discovered and developed to interrogate the biology of proteasome functions and to explore for treatment of various diseases . In this report, we described our discovery of a novel class of noncovalent inhibitors that selectively inhibit β5c of the constitutive proteasome over β5i of the immunoproteasome and their antimultiple myeloma activities and the synergistic effects with a noncovalent β5i-selective inhibitor.…”

Site-Specific Proteasome Inhibitors

“…Due to their essential role in the pathogenesis of M. tuberculosis and several eukaryotic parasites, e.g., Plasmodia, Leishmania, and Trypanosoma, proteasomes are considered drug targets for the treatment of tuberculosis, malaria, leishmaniasis, African sleeping sickness, and Chagas disease. A comprehensive review of selective inhibitors of mycobacterial and parasitic proteasomes has just been published [29], and this review will therefore focus on the inhibitors of mammalian proteasomes. Proteasomes are present in all eukaryotes, archaebacteria, and mycobacteria, including Mycobacterium tuberculosis.…”

Design, Synthesis, and Optimization of Macrocyclic Peptides as Species-Selective Antimalaria Proteasome Inhibitors

“…Mutations in parasite proteasomes that confer resistance to proteasome inhibitors show a fitness cost to some degree with increased susceptibility to artemisinins. − ,,− However, developing parasite proteasome-selective inhibitors is challenging . Proteasomes are highly conserved in eukaryotes, with 14 α and 14 β subunits arranged in a stack of four ringsα subunits forming the outer rings and β subunits forming the inner rings in α 1–7 β 1–7 β 1–7 α 1–7 fashion . In addition to interacting with multiple regulatory particles, such as 19S, PA28, and PA200, the outer α rings guard the entrance of substrate to the proteolytic chamber formed by the two inner β rings.…”

“…7−9,12,17−19 However, developing parasite proteasome-selective inhibitors is challenging. 20 Proteasomes are highly conserved in eukaryotes, with 14 α and 14 β subunits arranged in a stack of four ringsα subunits forming the outer rings and β subunits forming the inner rings in α 1−7 β 1−7 β 1−7 α 1−7 fashion. 20 In addition to interacting with multiple regulatory particles, such as 19S, PA28, and PA200, the outer α rings guard the entrance of substrate to the proteolytic chamber formed by the two inner β rings.…”