Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

Sailajah Gukathasan; Sean Parkin; Esther P. Black; Samuel G. Awuah

doi:10.1021/acs.inorgchem.1c01517

Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

Sailajah Gukathasan, Sean Parkin, Esther P. Black, Samuel G. Awuah

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

Transition-metal-based approaches to selectively modify proteins hold promise in addressing challenges in chemical biology. Unique bioorthogonal chemistry can be achieved with preformed metal-based compounds; however, their utility in native protein sites within cells remain underdeveloped. Here, we tune the ancillary ligands of cyclometalated gold(III) as a reactive group, and the gold scaffold allows for rapid modification of a desired cysteine residue proximal to the ligand binding site of a target protein. Moreover, evidence for a ligand association mechanism toward C-S bond formation by X-crystallography is established. The observed reactivity of cyclometalated gold(III) enables the rational design of a cysteine-targeted covalent inhibitor of mutant KRAS. This work illustrates the potential of structure-activity relationship studies to tune kinetics of cysteine arylation and rational design of metal-mediated ligand affinity chemistry (MLAC) of native proteins.

Original language	English
Pages (from-to)	14582-14593
Number of pages	12
Journal	Inorganic Chemistry
Volume	60
Issue number	19
DOIs	https://doi.org/10.1021/acs.inorgchem.1c01517
State	Published - Oct 4 2021

Bibliographical note

Funding Information:
We are grateful for the staff and facilities at the University of Kentucky that supported this work. This study made use of an NMR facility supported by NSF (CHE-9977388) as well as the UK X-ray facility with funds from the MRI program of the National Science Foundation (Grants CHE-0319176 and CHE-1625732). Thanks to the staff of Mass spectrometry facility, College of Arts and Sciences, University of Colorado Boulder, for running mass spectrometry samples. We are grateful for the use of Dr. Steven Van Lanen’s laboratory (UK College of Pharmacy) for the use of their Agilent 1200 LC-MS. We acknowledge Dr. Jong Hyun Kim for initial synthesis of compound 6 and 7 . Thanks to Dr. Samuel Ofori for helpful discussions regarding in silico studies and Dr. Jong Hyun Kim for the assistance of making complexes 6 and 7 .

Funding Information:
We are grateful to the University of Kentucky for funding. The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456).

Publisher Copyright:
©

ASJC Scopus subject areas

Physical and Theoretical Chemistry
Inorganic Chemistry

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10.1021/acs.inorgchem.1c01517

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title = "Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation",

abstract = "Transition-metal-based approaches to selectively modify proteins hold promise in addressing challenges in chemical biology. Unique bioorthogonal chemistry can be achieved with preformed metal-based compounds; however, their utility in native protein sites within cells remain underdeveloped. Here, we tune the ancillary ligands of cyclometalated gold(III) as a reactive group, and the gold scaffold allows for rapid modification of a desired cysteine residue proximal to the ligand binding site of a target protein. Moreover, evidence for a ligand association mechanism toward C-S bond formation by X-crystallography is established. The observed reactivity of cyclometalated gold(III) enables the rational design of a cysteine-targeted covalent inhibitor of mutant KRAS. This work illustrates the potential of structure-activity relationship studies to tune kinetics of cysteine arylation and rational design of metal-mediated ligand affinity chemistry (MLAC) of native proteins. ",

author = "Sailajah Gukathasan and Sean Parkin and Black, {Esther P.} and Awuah, {Samuel G.}",

note = "Funding Information: We are grateful for the staff and facilities at the University of Kentucky that supported this work. This study made use of an NMR facility supported by NSF (CHE-9977388) as well as the UK X-ray facility with funds from the MRI program of the National Science Foundation (Grants CHE-0319176 and CHE-1625732). Thanks to the staff of Mass spectrometry facility, College of Arts and Sciences, University of Colorado Boulder, for running mass spectrometry samples. We are grateful for the use of Dr. Steven Van Lanen{\textquoteright}s laboratory (UK College of Pharmacy) for the use of their Agilent 1200 LC-MS. We acknowledge Dr. Jong Hyun Kim for initial synthesis of compound 6 and 7 . Thanks to Dr. Samuel Ofori for helpful discussions regarding in silico studies and Dr. Jong Hyun Kim for the assistance of making complexes 6 and 7 . Funding Information: We are grateful to the University of Kentucky for funding. The authors acknowledge support of the Center for Pharmaceutical Research and Innovation (NIH P20 GM130456). Publisher Copyright: {\textcopyright} ",

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Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

Abstract

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