| TECHNOLOGY |
The Co.`s group uses mass spectrometry to both screen for compounds with binding affinity for an RNA target and to study in detail the nature of certain RNA-ligand interactions. To aid them in their quest for drugs targeting structured regions of RNA, they've developed a chemical strategy called SAR by MS as an alternative to high-throughput screening. "In conventional high-throughput screening for drug discovery, Co. tells "large numbers of existing compounds are screened against a new target to identify actives. However, when applied to RNA targets, the high-throughput approach has not been as productive as it has been with typical protein targets. "In our own high-throughput screening efforts, we have screened both commercially available as well as RNA-directed combinatorial libraries and found extremely low hit rates--less than 0.01%. Furthermore, the compounds discovered were often nonspecific in action and usually displayed poor structure-activity relationships"--that is, their properties couldn't easily be improved by structural modification. "Many of these problems can be traced to difficulties that traditional high-throughput screening assay formats have in detecting and accurately measuring the relatively weak interactions most small molecules have with RNA. Co. developed the SAR by MS assay methodology as an improved means for measuring ligand-RNA affinity. The technique is carried out by screening a set of ligands for binding affinity to an RNA of interest. Structural motifs shared by the compounds that bind RNA are identified, and specific mechanisms of binding are studied with additional MS experiments. Derivatives of the most promising ligands are then prepared by chemical modification, and the effects of these changes on binding are monitored. "This yields an extensive SAR pattern among the ligands assayed, which serves to guide elaboration to higher affinity ligands. "These types of experiments provide a data set of 'molecular rulers' that suggest a particular way to link two or more ligands together," he adds. "By successfully linking pairs of ligands with the appropriate chemical moiety, large improvements in binding affinity have been obtained." The Co.`s research team has already observed such affinity enhancements for many different ligands across multiple RNA targets. "Furthermore, the speed of the SAR by MS data cycle allows multiple iterations of the ligand linking sequence to be performed on a single target. "This allows the number of specific interactions with the target to be fine-tuned and provides for a simple and effective method to discover a new high-affinity ligand for any RNA target." |
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