PHOTOCATALYSIS IN BIOLOGICAL CONTEXTS: NOVEL METHODS FOR BIOCONJUGATION AND PROXIMITY LABELING

Abstract

Photocatalysis, in the broadest terms, is using light energy to lower the activation barrier of a reaction. Recent research in the MacMillan group focuses on photoredox catalysis, where a suitable light-activated catalyst enables reactivity via single electron transfer under visible-light irradiation at room temperature. Beyond the myriad of methods developed for small-molecule organic chemistry, photocatalysis also offers a novel perspective in inducing reactivity on biomolecules. Chapter 1 details the background and motivation toward applying photo and photoredox catalysis in biological contexts. Site-selective bioconjugation methods on native proteins are desirable in areas spanning cellular tracking, imaging, and the development of antibody-drug conjugates. Chapter 2 describes a photoredox-catalyzed methionine-selective alkylation reaction, which enables irreversible C–C bond formation while maintaining substrate integrity. Beyond chemoselectivity, regioselectivity in bioconjugation of endogenous proteins is a desirable, albeit seldomly achieved, goal. Chapter 3 presents a site-selective tyrosine bioconjugation reaction, in which specific tyrosine residues are selectively functionalized over other ones in the same native protein. Chapter 4 describes a novel strategy to enable uphill energy transfer via the biohybrid of a broad-spectrum light-harvesting protein and a canonical small-molecule photocatalyst. This invention enables red light (low energy) catalysis of reactions that are previously blue light (high energy) catalyzed. Since 2020, research in the MacMillan group expanded applying photocatalysis toward proximity labeling, the study of local cellular microenvironments. Chapters 5 describe efforts to study the KRAS pathway using this strategy.