Laboratory of Chemical Biology of Natural Products and Designed Molecules, Institute of Physical Chemistry, N.C.S.R. "Demokritos", 15310 Ag. Paraskevi Attikis, Athens, Greece.
Chembiochem. 2011 Jan 3;12(1):71-87. doi: 10.1002/cbic.201000591.
The bacterial ribosome represents the confirmed biological target for many known antibiotics that interfere with bacterial protein synthesis. Aminoglycosides represent a lead paradigm in RNA molecular recognition and constitute ideal starting points for the design and synthesis of novel RNA binders. Previous rational design approaches of RNA-targeting small molecules have been mainly concentrated on direct functionalization of aminoglycosidic substructures. Herein, we successfully designed and synthesized rigid spirocyclic scaffolds locked in a predicted ribosome-bound "bioactive" conformation. These analogues are able to mimic many of the interactions of the natural products for the A-site, as proven by their obtained binding affinities. The development of an optimized approach for their synthesis and their potential to inhibit protein production in vitro are presented. Our results could be further utilized for the development of analogues with improved antibiotic profiles.
细菌核糖体是许多已知抗生素的明确生物靶点，这些抗生素干扰细菌蛋白质合成。氨基糖苷类抗生素代表了 RNA 分子识别的主导范例，是设计和合成新型 RNA 结合物的理想起点。以前针对 RNA 靶向小分子的合理设计方法主要集中在氨基糖苷类结构的直接功能化上。在此，我们成功设计和合成了刚性螺环支架，其处于预测的核糖体结合的“生物活性”构象中。这些类似物能够模拟天然产物与 A 位的许多相互作用，这已通过它们获得的结合亲和力得到证明。本文介绍了其合成的优化方法的发展及其在体外抑制蛋白质产生的潜力。我们的研究结果可进一步用于开发具有改善的抗生素特性的类似物。
