Antiprotozoal Structure-Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action.

Brand, Michael; Wang, Lei; Agnello, Stefano; Gazzola, Silvia; Gall, Flavio M; Raguž, Luka; Kaiser, Marcel; Schmidt, Remo S; Ritschl, Amélie; Jelk, Jennifer; Hemphill, Andrew; Mäser, Pascal; Bütikofer, Peter; Adams, Michael; Riedl, Rainer (2021). Antiprotozoal Structure-Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action. Angewandte Chemie (International ed.), 60(28), pp. 15613-15621. Wiley-VCH 10.1002/anie.202102153

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
05 Veterinary Medicine > Department of Infectious Diseases and Pathobiology (DIP) > Institute of Parasitology

UniBE Contributor:

Wang, Lei; Jelk, Jennifer; Hemphill, Andrew and Bütikofer, Peter

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1433-7851

Publisher:

Wiley-VCH

Language:

English

Submitter:

Achim Braun Parham

Date Deposited:

09 Aug 2021 16:44

Last Modified:

09 Aug 2021 16:44

Publisher DOI:

10.1002/anie.202102153

PubMed ID:

33730410

Uncontrolled Keywords:

antiparasitic agent drug discovery medicinal chemistry mode of action peptides

BORIS DOI:

10.48350/157902

URI:

https://boris.unibe.ch/id/eprint/157902

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