1. [Amino acid and peptide derivatives of the tylosin family of macrolide antibiotics modified at the aldehyde group]
N V Sumbatian, I V Kuznetsova, V V Karpenko, N V Fedorova, V A Chertkov, G A Korshunova, A A Bogdanov Bioorg Khim. 2010 Mar-Apr;36(2):265-76. doi: 10.1134/s1068162010020159.
Fourteen new functionally active amino acid and peptide derivatives of the antibiotics tylosin, desmycosin, and 5-O-mycaminosyltylonolide were synthesized in order to study the interaction of the growing polypeptide chain with the ribosomal tunnel. The conjugation of various amino acids and peptides with a macrolide aldehyde group was carried out by two methods: direct reductive amination with the isolation of the intermediate Schiff bases or through binding via oxime using the preliminarily obtained derivatives of 2-aminooxyacetic acid.
2. New amidino-benzimidazolyl derivatives of tylosin and desmycosin
Marijana Hranjec, Kristina Starcević, Branimir Zamola, Stjepan Mutak, Marko Derek, Grace Karminski-Zamola J Antibiot (Tokyo). 2002 Mar;55(3):308-14. doi: 10.7164/antibiotics.55.308.
New amidino-benzimidazolyl derivatives of antibiotics tylosin and desmycosin are prepared in the reaction of corresponding amidino-substituted o-phenylendiamine with tylosin respectively desmyicosin on the 20-C aldehyde group. The reaction was carried out in absolute ethanol in the presence ofp-benzoquinone. On this way are prepared: 20-[5-(N-isopropylamidino)-2-benzimidazolyl]tylosin hydrochloride 9, 20-[5-(2-imidazolinyl)-2-benzimidazolyl]tylosin hydrochloride 10, 20-[5-(N-morpholinylamidino)-2-benzimidazolyl]tylosin hydrochloride 11, 20-[5-(N-isopropylamidino)-2-benzimidazolyl]desmycosin hydrochloride 12, 20-[5-(2-imidazolinyl)-2-benzimidazolyl]desmycosin hydrochloride 13, 20-[5-(N-morpholinylamidino)-2-benzimidazolyl]desmycosin hydrochloride 14. Their antimicrobial activity was tested on a series of microorganisms.
3. Conjugates of amino acids and peptides with 5-o-mycaminosyltylonolide and their interaction with the ribosomal exit tunnel
Anna Shishkina, Gennady Makarov, Andrey Tereshchenkov, Galina Korshunova, Nataliya Sumbatyan, Andrey Golovin, Maxim Svetlov, Alexey Bogdanov Bioconjug Chem. 2013 Nov 20;24(11):1861-9. doi: 10.1021/bc400236n. Epub 2013 Oct 25.
During protein synthesis the nascent polypeptide chain (NC) extends through the ribosomal exit tunnel (NPET). Also, the large group of macrolide antibiotics binds in the nascent peptide exit tunnel. In some cases interaction of NC with NPET leads to the ribosome stalling, a significant event in regulation of translation. In other cases NC-ribosome interactions lead to pauses in translation that play an important role in cotranslational folding of polypeptides emerging from the ribosome. The precise mechanism of NC recognition in NPET as well as factors that determine NC conformation in the ribosomal tunnel are unknown. A number of derivatives of the macrolide antibiotic 5-O-mycaminosyltylonolide (OMT) containing N-acylated amino acid or peptide residues were synthesized in order to study potential sites of NC-NPET interactions. The target compounds were prepared by conjugation of protected amino acids and peptides with the C23 hydroxyl group of the macrolide. These OMT derivatives showed high although varying abilities to inhibit the firefly luciferase synthesis in vitro. Three glycil-containing derivatives appeared to be strong inhibitors of translation, more potent than parental OMT. Molecular dynamics (MD) simulation of complexes of tylosin, OMT, and some of OMT derivatives with the large ribosomal subunit of E. coli illuminated a plausible reason for the high inhibitory activity of Boc-Gly-OMT. In addition, the MD study detected a new putative site of interaction of the nascent polypeptide chain with the NPET walls.