Pentelute Lab MIT | Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents
The Pentelute Lab aims to invent new chemistry for the efficient and selective modification of proteins, to ‘hijack’ these biological machines for efficient drug delivery into cells and to create new machines to rapidly and efficiently manufacture peptides and proteins.
Pentelute Lab, Chemistry, MIT, Chemistry Department, Boston, Cambridge, Biology, Peptides, Peptide, Proteins, Science, Rapid, Brad Pentelute, Brad,
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Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents

Oligonucleotide Bioconjugation with Bifunctional Palladium Reagents

First published: 17 March 2021 https://doi.org/10.1002/anie.202103180
Dr. Muhammad Jbara, Jacob Rodriguez, Dr. Heemal H. Dhanjee, Dr. Andrei Loas, Prof. Dr. Stephen L. Buchwald, Prof. Dr. Bradley L. Pentelute

Abstract

Organometallic reagents enable practical strategies for bioconjugation. Innovations in the design of water-soluble ligands and the enhancement of reaction rates have allowed for chemoselective cross-coupling reactions of peptides and proteins to be carried out in water. There are currently no organometallic-based methods for oligonucleotide bioconjugation to other biomolecules. Here we report bifunctional palladium(II)-oxidative addition complexes (OACs) as reagents for high-yielding oligonucleotide bioconjugation reactions. These bifunctional OACs react chemoselectively with amine-modified oligonucleotides to generate the first isolable, bench stable oligonucleotide-palladium(II) OACs. These complexes undergo site-selective C-S arylation with a broad range of native thiol-containing biomolecules at low micromolar concentrations in under one hour. This approach provided oligonucleotide-peptide, oligonucleotide-protein, oligonucleotide-small molecule, and oligonucleotide-oligonucleotide conjugates in >80 % yield and afforded conjugation of multiple copies of oligonucleotides onto a monoclonal antibody.

Category
2021, Publications