Drugging the “undruggable” by sampling a vast chemical space of membrane-permeable cyclic peptides

Objetivo

"Background and problem: Many disease targets, including a wide range of intracellular protein–protein interactions (PPIs), exhibit flat, featureless surfaces. This means that it is very difficult to develop small-molecule ligands against these targets and to modulate them therapeutically. Ultimately, thus, many major diseases for which therapeutic targets are known remain untreated. Small, non-polar cyclic peptides have aroused much excitement as an answer to this problem due to their ability to cross membranes and bind challenging targets. However, there are currently no methods for generating and screening sufficiently large and diverse libraries of membrane-permeable cyclic peptides.
Objectives and strategy/ideas: My goal is to drastically push the boundaries of library size and diversity. I will achieve this by generating pools of small, membrane-permeable cyclic peptides that are unprecedently large (> 100 million) and chemically diverse (> 1,000 different chemical building blocks) and will screen these peptides against challenging targets. I will employ DNA tagging to encode the libraries, a strategy that has proven highly effective for small molecules but not for peptide libraries due to technical challenges in synthesising molecules with so many building blocks. To address these barriers and enable the creation of DNA-encoded cyclic peptide libraries, I propose four novel strategies that I will apply to develop binders for important disease targets that have proven particularly challenging to drug, including STAT3, NF-κB, MYC, β-catenin, and IL-23R.
Outcome and impact: I anticipate that these new methods will yield membrane-permeable ligands for several of the named targets, providing urgently needed starting points for drug development. Most importantly, I expect to establish a powerful method that will be broadly applied in academia and industry. to a wide range of diseases currently tagged as ""undruggable,"" ultimately benefiting large numbers of patients."