Metal-Mediated Ligand Affinity Chemistry (MLAC)

Sailajah Gukathasan; Samuel G Awuah

doi:10.1007/978-1-0716-3469-1_6

Metal-Mediated Ligand Affinity Chemistry (MLAC)

Methods Mol Biol. 2024:2720:85-97. doi: 10.1007/978-1-0716-3469-1_6.

Authors

Sailajah Gukathasan¹, Samuel G Awuah^{2

3

4}

Affiliations

¹ Department of Chemistry, University of Kentucky, Lexington, KY, USA.
² Department of Chemistry, University of Kentucky, Lexington, KY, USA. awuah@uky.edu.
³ Center for Pharmaceutical Research and Innovation, College of Pharmacy and Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY, USA. awuah@uky.edu.
⁴ Markey Cancer Center, University of Kentucky, Lexington, KY, USA. awuah@uky.edu.

PMID: 37775659
DOI: 10.1007/978-1-0716-3469-1_6

Abstract

Metal-mediated ligand affinity chemistry (MLAC) enables site-specific protein modification and represents a powerful bioorthogonal strategy. Conventional bioorthogonal methods often involve two steps: (i) incorporation of the bioorthogonal handle (e.g., non-canonical amino acid, enzyme domain, peptide sequences) and (ii) the binding of functional molecules such as drugs, affinity tags, and fluorophores. This two-step protocol often involves genetic manipulation, which makes it impossible to chemically modify endogenous proteins in living systems. Thus, we propose the development of a transition metal-based chemical strategy that is ligand-directed to the endogenous protein of interest in a single step, which we refer to as metal-mediated ligand affinity chemistry (MLAC).

Keywords: Bioconjugation; MLAC; Metal-based covalent modification; Protein modification.