Targeting RNA-protein interactions with small molecules: promise and therapeutic potential
Curran A. Rhodes, Sumirtha Balaratnam, Kamyar Yazdani, Srinath Seshadri, John S. Schneekloth
Abstract
Abstract The therapeutic potential of targeting protein-RNA interactions has not been fully explored. While several approaches to block the interactions between various RNA and protein partners have been developed, rational efforts to target pre-assembled complexes have not been broadly pursued. This is despite the recent commercial success of risdiplam, and the high-resolution structure of the EIF4A-polypurine-Rocaglamide A ternary complex, which elucidates how compounds may recognize these pockets. These prominent examples indicate the viability of this approach, but important questions remain. For example, how abundant are these pockets in other protein-RNA complexes? Do such pockets have properties suitable for small molecule recognition? A broad analysis of 160 previously published RNP complexes confirmed that interfacial pockets in RNA-protein complexes are both abundant and have favorable properties that would make them good candidates for rational screening campaigns. These conclusions are expected to have important implications especially for those working on developing small molecules that bind directly to RNA structural elements.