Interaction of Chloramphenicol Cationic Peptide Analogues with the Ribosome
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Interaction of Chloramphenicol Cationic Peptide Analogues with the Ribosome Z. Z. Khairullina1#, A. G. Tereshchenkov2#, S. A. Zavyalova3, E. S. Komarova4,5, D. A. Lukianov5, V. N. Tashlitsky1, I. A. Osterman1,5, and N. V. Sumbatyan1* 1 Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia Belozersky Institute of PhysicoChemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia 3 Bach Institute of Biochemistry, Federal Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia 4 Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia 5 Skolkovo Institute of Science and Technology, 143025 Moscow, Russia a email: [email protected]
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Received July 13, 2020 Revised September 7, 2020 Accepted September 9, 2020 Abstract—Virtual screening of all possible tripeptide analogues of chloramphenicol was performed using molecular docking to evaluate their affinity to bacterial ribosomes. Chloramphenicol analogues that demonstrated the lowest calculated ener gy of interaction with ribosomes were synthesized. Chloramphenicol amine (CAM) derivatives, which contained specific peptide fragments from the prolinerich antimicrobial peptides were produced. It was demonstrated using displacement of the fluorescent erythromycin analogue from its complex with ribosomes that the novel peptide analogues of chlorampheni col were able to bind bacterial ribosome; all the designed tripeptide analogues and one of the chloramphenicol amine deriv atives containing fragment of the prolinerich antimicrobial peptides exhibited significantly greater affinity to Escherichia coli ribosome than chloramphenicol. Correlation between the calculated and experimentally evaluated levels of the ligand efficiencies was observed. In vitro protein biosynthesis inhibition assay revealed, that the RAWCAM analogue shows activ ity at the level of chloramphenicol. These data were confirmed by the chemical probing assay, according to which binding pattern of this analogue in the nascent peptide exit tunnel was similar to chloramphenicol. DOI: 10.1134/S0006297920110127 Keywords: ribosome, chloramphenicol, peptide derivatives, molecular docking, antimicrobial peptides, nascent peptide exit tunnel
INTRODUCTION Rapid evolution in the field of Xray crystallography over the last two decades and the possibility of creating atomic models of ribosome complexes with substrates and protein translation factors opened a new era in the inves tigation of the mechanisms of translation and its regula
tion [1, 2, 3]. The peptidyl transferase center (PTC) cat alyzing protein synthesis, and the ribosome nascent pep tide exit tunnel (NPET) supporting release of polypeptide are important structural elements of the ribosome [46]. While polypeptide chain moves along the NPET, its walls are involved in monitoring of the polypeptide sequence [4, 7, 8]. A large number of antibiotics with mechanism of
Abbreviations: Boc, tertbutoxycarbonyl; BODIPY, (4,4
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