Protein and peptide therapeutics are frequently employed for disease treatment, with more than 100 therapeutics garnering the Food and Drug Administration’s (FDA) approval for use in the clinic. Conjugation of synthetic polymers, such as polyethylene glycol (PEG), to biomolecule therapeutics often significantly increases the stability and in-vivo lifetime of the drug, making the application of proteins as disease treatments more feasible and effective. Bioconjugation techniques for protein-polymer conjugation are numerous, however, many of the linkages involve bonds that are considered weak and reversible in biological media. Additionally, slow kinetics and steric challenges generally necessitate large amounts of excess reagents, thereby increasing costs and making purification challenging. Organometallic transformations are known to circumvent these issues, however harsh reaction conditions, incompatibility in aqueous media and substrate promiscuity often limit their use in a biological context. This work demonstrates a facile and benign organometallic Au(III) S-arylation approach that enables the synthesis of mPEG-protein and mPEG-peptide conjugates with high efficiency. Isolable and bench-stable 2–10kDa mPEG-Au(III) reagents were synthesized via oxidative addition into terminal aryl iodide substituents on mPEG substrates with a MeDalPhosAu(I)Cl precursor. Reaction of the resulting mPEG-Au(III) reagents with a cysteine thiol on a biomolecule in aqueous buffer resulted in facile reductive elimination to forge a stable covalent S-aryl linkage, affording the mPEG-biomolecule conjugate. Notably, low polymer reagent loadings were used to achieve quantitative conversion at room temperature in a matter of minutes due to the rapid kinetics and high chemoselectivity of the reductive elimination step. The mild reaction conditions associated with this approach make it amenable to the synthesis of robust mPEG conjugates that are inaccessible through conventional methods, revealing their otherwise inaccessible potential as therapeutics.

Organometallic Au(III) reagents for protein-polymer conjugation

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