Olivier B. C. Monty; Pranavanand Nyshadham; Kurt Bohren; Murugesan Palaniappan; Martin M. Matzuk; Damian W. Young; Nicholas Simmons
ACS Comb. Sci., 2020, 22, 2, 80-88
https://doi.org/10.1021/acscombsci.9b00199

Abstract

Reaction heterogeneity, poor pH control, and catalyst decomposition in the ring-closing metathesis (RCM) of DNA–chemical conjugates leads to poor yields of the cyclized products. Herein we address these issues with a RCM reaction sys-tem 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 cy-clized product. Additionally, we provide a systematic study of the substrate scope of the on-DNA RCM reaction, a demon-stration 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.