title: Targeting proteasomes in infectious organisms to combat disease.
abstract: Proteasomes are multisubunit, energy-dependent, proteolytic complexes that play an essential role in intracellular protein turnover. They are present in eukaryotes, archaea, and in some actinobacteria species. Inhibition of proteasome activity has emerged as a powerful strategy for anticancer therapy and three drugs have been approved for treatment of multiple myeloma. These compounds react covalently with a threonine residue located in the active site of a proteasome subunit to block protein degradation. Proteasomes in pathogenic organisms such as Mycobacterium tuberculosis and Plasmodium falciparum also have a nucleophilic threonine residue in the proteasome active site and are therefore sensitive to these anticancer drugs. This review summarizes efforts to validate the proteasome in pathogenic organisms as a therapeutic target. We describe several strategies that have been used to develop inhibitors with increased potency and selectivity for the pathogen proteasome relative to the human proteasome. In addition, we highlight a cell-based chemical screening approach that identified a potent, allosteric inhibitor of proteasomes found in Leishmania and Trypanosoma species. Finally, we discuss the development of proteasome inhibitors as anti-infective agents.
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.|Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, CA, USA.
authors.forename: Betsaida
authors.initials: B
authors.lastname: Bibo-Verdugo
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.|Chemistry & Biochemistry Graduate Program, University of California San Diego, La Jolla, CA, USA.
authors.forename: Zhenze
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.|Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, CA, USA.
authors.forename: Conor R
authors.initials: CR
authors.lastname: Caffrey
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.|Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, CA, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: O'Donoghue
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D006801:Humans; D009161:Mycobacterium / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity; D010961:Plasmodium / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D012547:Schistosoma / Q000187:drug effects / Q000378:metabolism / Q000472:pathogenicity
chemical_list: D000890:Anti-Infective Agents; D046988:Proteasome Endopeptidase Complex
keywords: 
  Mycobacterium
  ; 
  Plasmodium
  ; 
  Schistosoma
  ; inhibitor; kinetoplastid; proteasome