Homogeneous and Functional Group Tolerant Ring-Closing Metathesis for DNA-Encoded Chemical Libraries

Authors

Olivier B C Monty
Pranavanand Nyshadham
Kurt M Bohren
Murugesan Palaniappan
Martin M Matzuk
Damian W Young
Nicholas Simmons

Publication Date

2-10-2020

Journal

ACS Combinatorial Science

DOI

10.1021/acscombsci.9b00199

PMID

31913011

PMCID

PMC7014401

PubMedCentral® Posted Date

1-8-2020

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Buffers, Catalysis, Cyclization, DNA, Gene Library, Peptides, Small Molecule Libraries

Abstract

Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates lead to poor yields of the cyclized products. Herein we address these issues with a RCM reaction system that includes a novel aqueous solvent combination to enable reaction homogeneity, an acidic buffer system which masks traditionally problematic functional groups, and a decomposition-resistant catalyst which maximizes conversion to the cyclized product. Additionally, we provide a systematic study of the substrate scope of the on-DNA RCM reaction, a demonstration of its applicability to a single-substrate DNA-encoded chemical library that includes sequencing analysis, and the first successful stapling of an unprotected on-DNA [i, i+4] peptide.

Comments

Associated Data