Bioinspired Design of Lysolytic Triterpenoid-Peptide Conjugates that Kill African Trypanosomes.

Autor: Leeder WM; Molecular Genetics, Darmstadt University of Technology, Schnittspahnstrasse 10, 64287, Darmstadt, Germany., Giehler F; Molecular Genetics, Darmstadt University of Technology, Schnittspahnstrasse 10, 64287, Darmstadt, Germany.; Present address: Helmholtz Zentrum München für Gesundheit und Umwelt (GmbH), Research Unit Gene Vectors Munich (Germany) and, German Center for Infection Research (DZIF), Partner Site Munich, Marchionistrasse 25, 81377, Munich, Germany., Joswig J; Molecular Genetics, Darmstadt University of Technology, Schnittspahnstrasse 10, 64287, Darmstadt, Germany., Göringer HU; Molecular Genetics, Darmstadt University of Technology, Schnittspahnstrasse 10, 64287, Darmstadt, Germany.
Jazyk: angličtina
Zdroj: Chembiochem : a European journal of chemical biology [Chembiochem] 2019 May 15; Vol. 20 (10), pp. 1251-1255. Date of Electronic Publication: 2019 Apr 01.
DOI: 10.1002/cbic.201800674
Abstrakt: Humans have evolved a natural immunity against Trypanosoma brucei infections, which is executed by two serum (lipo)protein complexes known as trypanolytic factors (TLF). The active TLF ingredient is the primate-specific apolipoprotein L1 (APOL1). The protein has a pore-forming activity that kills parasites by lysosomal and mitochondrial membrane fenestration. Of the many trypanosome subspecies, only two are able to counteract the activity of APOL1; this illustrates its evolutionarily optimized design and trypanocidal potency. Herein, we ask whether a synthetic (syn) TLF can be synthesized by using the design principles of the natural TLF complexes but with different chemical building blocks. We demonstrate the stepwise development of triterpenoid-peptide conjugates, in which the triterpenoids act as a cell-binding, uptake and lysosomal-transport modules and the synthetic peptide GALA acts as a pH-sensitive, pore-forming lysolytic toxin. As designed, the conjugate kills infective-stage African trypanosomes through lysosomal lysis thus demonstrating a proof-of-principle for the bioinspired, forward-design of a synTLF.
(© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
Externí odkaz: