| Autor: |
Brinkmann S; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, Giessen 35392, Germany., Semmler S; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, Giessen 35392, Germany., Kersten C; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz 55128, Germany., Patras MA; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, Giessen 35392, Germany., Kurz M; Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main 65926, Germany., Fuchs N; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz 55128, Germany., Hammerschmidt SJ; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz 55128, Germany., Legac J; Department of Medicine, University of California, San Francisco, California 94143, United States., Hammann PE; Evotec International GmbH, Göttingen 37079, Germany., Vilcinskas A; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, Giessen 35392, Germany.; Institute for Insect Biotechnology, Justus-Liebig-University of Giessen, Giessen 35392, Germany., Rosenthal PJ; Department of Medicine, University of California, San Francisco, California 94143, United States., Schirmeister T; Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University Mainz, Mainz 55128, Germany., Bauer A; Sanofi-Aventis Deutschland GmbH, R&D, Frankfurt am Main 65926, Germany., Schäberle TF; Fraunhofer Institute for Molecular Biology and Applied Ecology (IME), Branch for Bioresources, Giessen 35392, Germany.; Institute for Insect Biotechnology, Justus-Liebig-University of Giessen, Giessen 35392, Germany. |
| Abstrakt: |
Protease inhibitors represent a promising therapeutic option for the treatment of parasitic diseases such as malaria and human African trypanosomiasis. Falcitidin was the first member of a new class of inhibitors of falcipain-2, a cysteine protease of the malaria parasite Plasmodium falciparum . Using a metabolomics dataset of 25 Chitinophaga strains for molecular networking enabled identification of over 30 natural analogues of falcitidin. Based on MS/MS spectra, they vary in their amino acid chain length, sequence, acyl residue, and C-terminal functionalization; therefore, they were grouped into the four falcitidin peptide families A-D. The isolation, characterization, and absolute structure elucidation of two falcitidin-related pentapeptide aldehyde analogues by extensive MS/MS spectrometry and NMR spectroscopy in combination with advanced Marfey's analysis was in agreement with the in silico analysis of the corresponding biosynthetic gene cluster. Total synthesis of chosen pentapeptide analogues followed by in vitro testing against a panel of proteases revealed selective parasitic cysteine protease inhibition and, additionally, low-micromolar inhibition of α-chymotrypsin. The pentapeptides investigated here showed superior inhibitory activity compared to falcitidin. |
