# Synthesis and screening of DNA-encoded Libraries of Non-Peptidic Macrocycles

> **NIH NIH R44** · DELUGE BIOTECHNOLOGIES, INC. · 2022 · $734,020

## Abstract

Project Summary
Most drugs target proteins with relatively deep pockets, such as enzyme active sites. However, screening
collections comprised of these traditional Rule of 5-compliant molecules have consistently failed to provide high
quality drug leads for many targets that function via protein-nucleic acid and protein-protein interactions (PPIs).
These are the “difficult” or “undruggable” protein targets, which by some estimates comprise up to 85% of the
human proteome. The importance of these types of PPIs has been well noted in cancer therapeutics and more
recently in the infectious diseases field where PPIs play a role in the interaction between host and pathogen.
Macrocyclic peptides (MPs) are capable of engaging these shallow, solvent exposed surfaces, but most MPs are
not cell permeable. This highlights the critical need for the development of libraries of novel, cell permeable
compounds capable of engaging PPI surfaces. In Phase I, we successfully demonstrated the feasibility of
generating and screening large DNA-encoded libraries of non-peptidic macrocycles, which have the appropriate
characteristics to address this need. In this Phase II project, we will expand the chemical diversity of these
libraries, test them against several difficult targets, and establish methods to evolve primary screening hits
derived from the libraries into high-quality drug leads.

## Key facts

- **NIH application ID:** 10485271
- **Project number:** 5R44GM134785-03
- **Recipient organization:** DELUGE BIOTECHNOLOGIES, INC.
- **Principal Investigator:** Eric Koesema
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $734,020
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10485271

## Citation

> US National Institutes of Health, RePORTER application 10485271, Synthesis and screening of DNA-encoded Libraries of Non-Peptidic Macrocycles (5R44GM134785-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10485271. Licensed CC0.

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