Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N-Terminal Protein Modification

TY - JOUR

T1 - Effect of Pyridinecarboxaldehyde Functionalization on Reactivity and N-Terminal Protein Modification

AU - Barber, Lydia J.

AU - Stankevich, Ksenia S.

AU - Spicer, Christopher D.

N1 - Publisher Copyright: © 2025 The Authors. Published by American Chemical Society.

PY - 2025/4/4

Y1 - 2025/4/4

N2 - The site-selective modification of protein N-termini represents a powerful strategy for producing homogeneous bioconjugates. 2-Pyridinecarboxaldehydes have emerged as a leading reagent class in this area. However, these conjugations suffer from relatively slow rates and a degree of reversibility. In this work, we therefore studied the effects of pyridinecarboxaldehyde functionalization on N-terminal modification. This allowed us to provide insight into the factors governing relative contributions from competing reaction pathways and design criteria for second generation reagents for protein labeling. Importantly, 3-methoxy-2-pyridinecarboxaldehydes were identified as providing both accelerated and more stable protein labeling, enabling further applications of this powerful technology.

AB - The site-selective modification of protein N-termini represents a powerful strategy for producing homogeneous bioconjugates. 2-Pyridinecarboxaldehydes have emerged as a leading reagent class in this area. However, these conjugations suffer from relatively slow rates and a degree of reversibility. In this work, we therefore studied the effects of pyridinecarboxaldehyde functionalization on N-terminal modification. This allowed us to provide insight into the factors governing relative contributions from competing reaction pathways and design criteria for second generation reagents for protein labeling. Importantly, 3-methoxy-2-pyridinecarboxaldehydes were identified as providing both accelerated and more stable protein labeling, enabling further applications of this powerful technology.

KW - aldehyde

KW - aqueous chemistry

KW - bioconjugation

KW - imine

KW - protein

KW - reversible reaction

UR - http://www.scopus.com/inward/record.url?scp=105001934834&partnerID=8YFLogxK

U2 - 10.1021/jacsau.5c00238

DO - 10.1021/jacsau.5c00238

M3 - Article

AN - SCOPUS:105001934834

SN - 2691-3704

JO - JACS Au

JF - JACS Au

ER -