US Patent 12077795 Method for biocatalytic protein-oligonucleotide conjugation

A composition comprising a polypeptide ligated to an oligonucleotide through a sterol linker. A method of ligating a polypeptide to an oligonucleotide, comprising a polypeptide having a hedgehog steroyl transferase catalytic domain at the C-terminal of the polypeptide with an electrophilic residue, e.g., glycine, between polypeptide and the hedgehog steroyl transferase catalytic domain, and a steroylated oligonucleotide in solution, and permitting a reaction to cleave the hedgehog steroyl transferase catalytic domain from the polypeptide while ligating the steroylated oligonucleotide to the glycine at the C-terminal of the polypeptide. The oligonucleotide may be, for example, a therapeutic, diagnostic, or affinity ligand.