RRM
2009 Rustbelt RNA Meeting
RRM
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Talk abstracts
Abstract:
The ribosome is a potential target for several classes of antibiotics because of its accessibility and structural diversity. Different classes of antibiotics bind to different sites within the ribosome to inhibit the ribosomal assembly and translation. Bacteria have become resistant to most of the known antibiotics; therefore, it is important to design and develop new therapeutic agents. The first step towards the development of a drug is to find ideal targets sites that are not only functionally important, but also accessible to various compounds. Most of the available chemical reagents that have been used to probe RNA structure are limited to in vitro studies due to inability to penetrate the cell wall, high toxicity and or challenges in detection of their reactive sites. Cisplatin, cis-[Pt(NH3)2Cl2], reacts preferentially with purine bases in DNA and RNA and forms various adducts, such as 1,2-GpG-intrastrand cross-links. The adducts formed in the ribosome will give information about accessibility of the nucleotides within the complex 3D structure. We have utilized cisplatin to probe accessible guanine residues in RNA model systems, 16S rRNA, and the ribosome. This method has several advantages over other chemical probes: the adducts are easily detected, and the probe can be used in vivo. In addition, to study the effects of electrostatic interactions and compare the binding sites and reactivity with the cisplatin, we have synthesized a variety of amino-acid-linked platinum complexes. The binding sites of these complexes are distinctly different from those of the parental compound cisplatin. We demonstrate that platinum complexes have the ability to provide information about helix or loop accessibility in the ribosome. Investigation of accessible and functionally important target sites in the ribosome will play a significant role in the design of novel drug leads.
Keywords: Ribosome, Cisplatin, Probing
