Exploiting translational stalling peptides in an effort to extend azithromycin interaction within the prokaryotic ribosome nascent peptide exit tunnel.
Exploiting translational stalling peptides in an effort to extend azithromycin interaction within the prokaryotic ribosome nascent peptide exit tunnel.
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DOI：
10.1016/j.bmc.2015.04.078
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发表时间：
2015-08-15
影响因子：
3.5
通讯作者：
Oyelere AK
中科院分区：
文献类型：
--
作者：
Washington AZ;Tapadar S;George A;Oyelere AK
核糖体是细胞中主要的蛋白质合成机器，并且是治疗包括细菌感染和癌症在内的多种疾病的靶标。核糖体肽出口通道是新生肽的出口途径，是药物设计的一个诱人位点。为了合理地结合新生肽组分以设计核糖体功能的小分子抑制剂，我们在本文中设计并公开了一组N-10吲哚官能化的阿奇霉素类似物。设计这些化合物的吲哚部分以模拟SecM W155侧链与原核（大肠杆菌）核糖体A751残基的翻译停滞相互作用。这些N-10官能化化合物中的许多相对于阿奇霉素具有增强的针对大肠杆菌核糖体的翻译抑制活性，而一个子集抑制代表性敏感细菌菌株的生长至与阿奇霉素大致相同的程度。此外，在细菌生长培养基中包含牛血清将N-10官能化阿奇霉素类似物的抗菌效力提高了高达10倍。
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 (E.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.