title: Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors.
abstract: Despite declining numbers of cases and deaths, malaria remains a major public health problem in many parts of the world. Today, case management relies heavily on a single class of antimalarial compounds: artemisinins. Hence, development of resistance against artemisinins may destroy current malaria control strategies. Beyond malaria control are elimination and eradication programs that will require drugs with good activity against acute infection but also with preventive and transmission-blocking properties. Consequently, new antimalarials are needed not only to ensure malaria control but also for elimination and eradication efforts. In this study, we introduce peptido sulfonyl fluorides (PSF) as a new class of compounds with antiplasmodial activity. We show that PSF target the plasmodial proteasome and act on all asexual stages of the intraerythrocytic cycle and on gametocytes. PSF showed activities at concentrations as low as 20 nM against multidrug-resistant and chloroquine-sensitive Plasmodium falciparum laboratory strains and clinical isolates from Gabon. Structural requirements for activity were identified, and cytotoxicity in human HeLa or HEK 293 cells was low. The lead PSF PW28 suppressed growth of Plasmodium berghei in vivo but showed signs of toxicity in mice. Considering their modular structure and broad spectrum of activity against different stages of the plasmodial life cycle, proteasome inhibitors based on PSF have a great potential for further development as preclinical candidate compounds with improved species-specific activity and less toxicity.
authors.affiliation: University of Tübingen, Institute of Tropical Medicine, and German Centre for Infection Research, Tübingen, Germany.
authors.forename: Serena
authors.initials: S
authors.lastname: Tschan
authors.forename: Arwin J
authors.initials: AJ
authors.lastname: Brouwer
authors.forename: Paul R
authors.initials: PR
authors.lastname: Werkhoven
authors.forename: Anika M
authors.initials: AM
authors.lastname: Jonker
authors.forename: Lena
authors.initials: L
authors.lastname: Wagner
authors.forename: Sarah
authors.initials: S
authors.lastname: Knittel
authors.forename: Makoah Nigel
authors.initials: MN
authors.lastname: Aminake
authors.forename: Gabriele
authors.initials: G
authors.lastname: Pradel
authors.forename: Fanny
authors.initials: F
authors.lastname: Joanny
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.forename: Benjamin
authors.initials: B
authors.lastname: Mordmüller
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005260:Female; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009842:Oligopeptides / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D052939:Schizonts / Q000187:drug effects; D013441:Sulfinic Acids / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D007976:Leupeptins; D009842:Oligopeptides; D061988:Proteasome Inhibitors; D013441:Sulfinic Acids; C048899:sulfuryl fluoride; D002738:Chloroquine; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde; C078846:epoxomicin