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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Broad-spectrum antimalarial activity of peptido sulfonyl fluorides, a new class of proteasome inhibitors
Antimicrobial Agents and Chemotherapy, Volume 57, No. 8, Year 2013
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Description
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. © 2013, American Society for Microbiology. All Rights Reserved.
Available Materials
https://efashare.b-cdn.net/share/pmc/articles/PMC3719782/bin/supp_57_8_3576__index.html
https://efashare.b-cdn.net/share/pmc/articles/PMC3719782/bin/AAC.00742-12_zac999101998so1.pdf
Authors & Co-Authors
Tschan, Serena C.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Brouwer, Arwin J.
Netherlands, Utrecht
Utrechts Instituut Voor Farmaceutische Wetenschappen
Werkhoven, Paul R.
Netherlands, Utrecht
Utrechts Instituut Voor Farmaceutische Wetenschappen
Jonker, Anika M.
Netherlands, Utrecht
Utrechts Instituut Voor Farmaceutische Wetenschappen
Wagner, Lena
Gabon, Lambarene
Centre de Recherches Médicales de Lambaréné
Knittel, Sarah
Gabon, Lambarene
Centre de Recherches Médicales de Lambaréné
Makoah, Nigel A.
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Germany, Aachen
Rheinisch-westfälische Technische Hochschule Aachen
Pradel, Gabriele
Germany, Wurzburg
Julius-maximilians-universität Würzburg
Germany, Aachen
Rheinisch-westfälische Technische Hochschule Aachen
Joanny, Fanny
Germany, Tubingen
Eberhard Karls Universität Tübingen
Gabon, Lambarene
Centre de Recherches Médicales de Lambaréné
Liskamp, Rob M.J.
Netherlands, Utrecht
Utrechts Instituut Voor Farmaceutische Wetenschappen
United Kingdom, Glasgow
University of Glasgow
Mordmüller, Benjamin G.
Germany, Tubingen
Eberhard Karls Universität Tübingen
Gabon, Lambarene
Centre de Recherches Médicales de Lambaréné
Statistics
Citations: 23
Authors: 11
Affiliations: 6
Identifiers
Doi:
10.1128/AAC.00742-12
ISSN:
00664804
e-ISSN:
10986596
Research Areas
Infectious Diseases
Study Locations
Gabon