Advancing the basic science of membrane permeability in macrocyclic peptides

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Macrocyclic peptides (MCPs) can demonstrate antibody-like potency and specificity against "undruggable" targets such as protein-protein interactions. Some MPCs, especially ones found in nature, also have drug-like cell permeability and even oral absorption, leading to the proposition that MCPs define a fertile ground for the discovery of novel, cell permeable inhibitors against undruggable targets. My lab is among the leaders in the worldwide effort to define the factors that govern passive membrane permeability in MCPs. In addition to defining a set of rules for generating molecules in this space, we have shown that existing macrocyclic natural products represent only a tiny fraction of potential permeable scaffolds in this size range (MW 700-1500). As the basic science of membrane permeability in MCPs has continued to mature, new questions have arisen which our lab is uniquely positioned to address: To what extent can side chains sequester polar backbone atoms in the membrane, and, conversely, to what extent can polar side chain functionality be "smuggled" into the membrane via interactions with backbone atoms? Are there scaffold geometries that enhance these effects? What is the fundamental size limit to passive membrane permeability? To what extent can strongly ionizable groups be incorporated into lipophilic MCPs without abrogating permeability? Can DNA-encoded library technology be used to discover novel, membrane permeable scaffolds that greatly enhance the extent to which we can evaluate this chemical space, especially in the higher MW range? Our program will capitalize on recent developments in DNA-encoded library (DEL) technology to generate large (108 - 1012-member) libraries that are diversified at both the side chain and backbone levels. We have shown that DNA-conjugated MCPs can be separated chromatographically based on the permeability of the pendant macrocycle and independent of the encoding DNA molecule, allowing us to use the power of split-pool synthesis and next- generation sequencing to dramatically expand our ability to delineate the constraints on permeability among highly diverse scaffolds well above 1000 MW. Finally, there have been few systematic studies on the impact of scaffold geometry on efflux and hepatic metabolism, which, besides permeability, are important factors that govern pharmacokinetic behavior. We will utilize our powerful split-pool synthesis and MSMS-analytical tool to determine the effect of scaffold geometry on efflux and metabolism, which will further enhance our understanding of this important chemical space. This MIRA proposal seeks to build on a vibrant and successful research program to uncover the basic scientific principles governing drug-like properties in a chemical class that continues to inspire medicinal chemists in their pursuit of ever more challenging targets.