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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|
Schmidt, Remo S.
|Published in:||Angewandte Chemie: International Edition|
|Publisher / Ed. Institution:||Wiley|
|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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|2021_Brand-etal_Antiprotozoal-structure–activity-relationships-of-synthetic-leucinostatin-derivatives.pdf||1.53 MB||Adobe PDF|
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Brand, M., Wang, L., Agnello, S., Gazzola, S., Gall, F., Raguž, L., Kaiser, M., Schmidt, R. S., Ritschl, A., Jelk, J., Hemphill, A., Mäser, P., Bütikofer, P., Adams, M., & Riedl, R. (2021). Antiprotozoal structure–activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action. Angewandte Chemie: International Edition, 60(28), 15613–15621. https://doi.org/10.1002/anie.202102153
Brand, M. et al. (2021) ‘Antiprotozoal structure–activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action’, Angewandte Chemie: International Edition, 60(28), pp. 15613–15621. Available at: https://doi.org/10.1002/anie.202102153.
M. Brand et al., “Antiprotozoal structure–activity relationships of synthetic leucinostatin derivatives and elucidation of their mode of action,” Angewandte Chemie: International Edition, vol. 60, no. 28, pp. 15613–15621, Mar. 2021, doi: 10.1002/anie.202102153.
Brand, Michael, et al. “Antiprotozoal Structure–Activity Relationships of Synthetic Leucinostatin Derivatives and Elucidation of Their Mode of Action.” Angewandte Chemie: International Edition, vol. 60, no. 28, Mar. 2021, pp. 15613–21, https://doi.org/10.1002/anie.202102153.
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