Fragments vs RNA

One of the promises of fragment-based methods is that they can tackle “hard” targets such as protein-protein interactions and nucleic acids. But going after these unconventional targets may require new libraries. A new paper in J. Med. Chem. sets out to do just this for RNA.

There are a few previous reports of discovering fragments that bind to RNA and their subsequent optimization; Ibis Therapeutics was particularly active in this field a few years back. In the current study, Fareed Aboul-ela and coworkers at Louisiana State University started by analyzing 120 known RNA-binding ligands and comparing these to known drugs and publicly available compounds. A variety of computationally derived physicochemical descriptors failed to differentiate the RNA binders from other molecules, but the authors note that:

This result does not preclude the likelihood that a finite set of chemical moieties constitute a “privileged” RNA binding set. The special properties of these functionalities may be too subtle or complex to detect using standard descriptors.

Following up on this hypothesis, the authors computationally “cleaved” their RNA binders to generate a set of fragments, and then purchased just over a hundred of these. These were then screened using four different NMR experiments to see if any bound to a 27-residue oligonucleotide derived from E. coli 16S rRNA, an important antibiotic target. Happily, five fragments were identified as binding to the RNA target, two of which had not previously been identified in the literature.

Whether these fragments can be advanced to high affinity binders, and whether the library will be generally useful against RNA, remain open questions. But one nice feature of this paper is the complete list of fragments tested provided in the supporting information. This list will allow other researchers to easily assemble their own screening set and test its utility. And if it proves useful, perhaps it will one day be sold by one of the commercial suppliers of fragments.