UC Santa Cruz

Cyclic peptides in the beyond rule of 5 space are increasingly gaining traction as a therapeutic platform, and their astonishing passive permeability and ability to bind difficult or “undruggable” targets is continually studied, developed, and exploited as potent lead drug compounds. RNA, as a cellular information carrier and gene regulator, has been implicated in many human diseases. The therapeutic potential of targeting RNA with drug-like molecules is being increasingly recognized and explored, but the physicochemical properties required to selectively target RNA from a membrane-permeable, therapeutically relevant paradigm remain unprobed, especially important considering existing efforts have yielded compounds that are largely antithetical to membrane permeability. We investigated the possibility of lipophilic, cell-permeable cyclic peptides binding RNA with high affinity and specificity. Chapter 1 describes the design and deployment of two choice cyclic peptides against a library of randomized RNAs to yield an RNA aptamer to each cyclic peptide that binds with high affinity and specificity. Sequence level apo and holo chemical probing efforts reveal crucial differences between the two complexes.

In a collaborative effort with the Theodore Holman lab (UC Santa Cruz), chapter 2 describes attempts towards the medicinal chemistry optimization of SLUG01, a derivative of a ML355, a previously reported human 12-Lipoxygenase inhibitor.