2. Academic Validation
  3. Antiprotozoal Structure-Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of their Mode of Action

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

  • Angew Chem Int Ed Engl. 2021 Jul 5;60(28):15613-15621. doi: 10.1002/anie.202102153.
Michael Brand 1,  Lei Wang 2,  Stefano Agnello 1,  Silvia Gazzola 1,  Flavio M Gall 1,  Luka Raguž 1,  Marcel Kaiser 3 4,  Remo S Schmidt 3 4,  Amélie Ritschl 3 4,  Jennifer Jelk 2,  Andrew Hemphill 5,  Pascal Mäser 3 4,  Peter Bütikofer 2,  Michael Adams 6,  Rainer Riedl 1
Affiliations

Affiliations

  • 1 Institute of Chemistry and Biotechnology, Center for Organic and Medicinal Chemistry, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820, Wädenswil, Switzerland.
  • 2 Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, 3012, Bern, Switzerland.
  • 3 Swiss Tropical and Public Health Institute, Socinstrasse 57, 4051, Basel, Switzerland.
  • 4 University of Basel, Petersplatz 1, 4001, Basel, Switzerland.
  • 5 Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, 3012, Bern, Switzerland.
  • 6 Bacoba AG, Elisabethenstrasse 15, 4051, Basel, Switzerland.
PMID: 33730410 DOI: 10.1002/anie.202102153
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.

Keywords

antiparasitic agent; drug discovery; medicinal chemistry; mode of action; peptides.

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