Exploiting translational stalling peptides in an effort to extend azithromycin interaction within the prokaryotic ribosome nascent peptide exit tunnel.

Autor: Washington AZ; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA., Tapadar S; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA., George A; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA., Oyelere AK; School of Chemistry and Biochemistry, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA; Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332-0400, USA. Electronic address: aoyelere@gatech.edu.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2015 Aug 15; Vol. 23 (16), pp. 5198-209. Date of Electronic Publication: 2015 May 06.
DOI: 10.1016/j.bmc.2015.04.078
Abstrakt: The ribosome is the primary protein synthesis machine in the cell and is a target for treatment of a variety of diseases including bacterial infection and cancer. The ribosomal peptide exit tunnel, the route of egress for the nascent peptide, is an inviting site for drug design. Toward a rational engagement of the nascent peptide components for the design of small molecule inhibitors of ribosome function, we designed and disclosed herein a set of N-10 indole functionalized azithromycin analogs. The indole moiety of these compounds is designed to mimic the translation stalling interaction of SecM W155 side-chain with the prokaryotic (Escherichia coli) ribosome A751 residue. Many of these N-10 functionalized compounds have enhanced translation inhibition activities against E. coli ribosome relative to azithromycin while a subset inhibited the growth of representative susceptible bacteria strains to about the same extent as azithromycin. Moreover, the inclusion of bovine serum in the bacterial growth media enhanced the anti-bacterial potency of the N-10 functionalized azithromycin analogs by as high as 10-fold.
(Published by Elsevier Ltd.)
Databáze: MEDLINE
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