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Antiprotozoal structure-activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 4646511
Author(s) Brand, M.; Wang, L.; Agnello, S.; Gazzola, S.; Gall, F. M.; Raguz, L.; Kaiser, M.; Schmidt, R. S.; Ritschl, A.; Jelk, J.; Hemphill, A.; Mäser, P.; Butikofer, P.; Adams, M.; Riedl, R.
Author(s) at UniBasel Kaiser, Marcel
Schmidt, Remo
Ritschl, Amélie
Mäser, Pascal
Year 2021
Title Antiprotozoal structure-activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action
Journal Angewandte Chemie
Volume 60
Number 28
Pages / Article-Number 15613-15621
Keywords antiparasitic agent; drug discovery; medicinal chemistry; mode of action; peptides
Mesh terms Antimicrobial Cationic Peptides, pharmacology; Antiprotozoal Agents, pharmacology; Molecular Conformation; Parasitic Sensitivity Tests; Structure-Activity Relationship; Trypanosoma brucei brucei, genetics
Abstract Leucinostatin A is one of the most potent antiprotozoal compounds ever described, but little was known on structure-activity relationships (SAR). We used Trypanosoma brucei as a protozoal model organism to test synthetically modified derivatives, resulting in simplified but equally active compounds 2 (ZHAWOC6025) and 4 (ZHAWOC6027), which were subsequently modified in all regions of the molecule to gain an in-depth SAR understanding. The antiprotozoal SAR matched SAR in phospholipid liposomes, where membrane integrity, leaking, and dynamics were studied. The mode of action is discussed based on a structure-activity analysis of derivatives in efficacy, ultrastructural studies in T. brucei , and artificial membrane models, mimicking membrane stability and membrane potential. The main site of antiprotozoal action of natural and synthetic leucinostatins lies in the destabilization of the inner mitochondrial membrane, as demonstrated by ultrastructural analysis, electron microscopy and mitochondrial staining. Long-time sublethal exposure of T. brucei (200 passages) and siRNA screening of 12000 mutants showed no signs of resistance development to the synthetic derivatives.
ISSN/ISBN 1521-3773
URL https://doi.org/10.1002/anie.202102153
edoc-URL https://edoc.unibas.ch/88978/
Full Text on edoc Available
Digital Object Identifier DOI 10.1002/anie.202102153
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/33730410
ISI-Number WOS:000648679100001
Document type (ISI) Journal Article
 
   

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