Engineered aldehyde dehydrogenases for amide bond formation

Lei Gao, Xiang Qiu, Jun Yang, Kangdelong Hu, Peilin Li, Wei Li, Feng Gao, Fabrice Gallou , Florian Kleinbeck, and Xiaoguang Lei

Science 2026

https://www.science.org/doi/10.1126/science.adw3365

Abstract

Amide bonds are among the most common structural motifs in pharmaceuticals. One-hundred seventeen out of the top 200 small-molecule drugs by retail sales in 2023 contain at least one amide bond. Half of the chemical transformations used in medicinal and process chemistry focus on amide coupling reactions in drug development. However, conventional chemical synthesis typically relies on activated carboxylic acid derivatives produced using stoichiometric or large excess coupling reagents. These strategies generate considerable waste, limit substrate scope, and compromise atom economy. Developing more efficient and sustainable methods for amide synthesis is, therefore, highly desirable. In this work, we repurposed aldehyde dehydrogenases (ALDHs) into oxidative amidases (OxiAms), which directly form an amide by coupling aldehydes and amines through oxidative amidation.