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Publication type: Article in scientific journal
Type of review: Peer review (publication)
Title: Antiprotozoal structure–activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action
Authors: Brand, Michael
Wang, Lei
Agnello, Stefano
Gazzola, Silvia
Gall, Flavio
Raguž, Luka
Kaiser, Marcel
Schmidt, Remo S.
Ritschl, Amélie
Jelk, Jennifer
Hemphill, Andrew
Mäser, Pascal
Bütikofer, Peter
Adams, Michael
Riedl, Rainer
et. al: No
DOI: 10.1002/anie.202102153
Published in: Angewandte Chemie: International Edition
Volume(Issue): 60
Issue: 28
Page(s): 15613
Pages to: 15621
Issue Date: 17-Mar-2021
Publisher / Ed. Institution: Wiley
ISSN: 1433-7851
Language: English
Subjects: Antiparasitic agent; Drug discovery; Medicinal chemistry; Mode of action; Peptides
Subject (DDC): 540: Chemistry
615: Pharmacology and therapeutics
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 12'000 mutants showed no signs of resistance development to the synthetic derivatives.
Fulltext version: Published version
License (according to publishing contract): CC BY-NC-ND 4.0: Attribution - Non commercial - No derivatives 4.0 International
Departement: Life Sciences and Facility Management
Organisational Unit: Institute of Chemistry and Biotechnology (ICBT)
Published as part of the ZHAW project: A topical anti-infective
New antileishmanial and antitrypanosomal drugs
New drugs for the treatment of protozoal infections derived from natural products
Appears in collections:Publikationen Life Sciences und Facility Management

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