Site-Specific Generation of Protein-Protein Conjugates Using Native Amino Acids
semanticscholar(2019)
摘要
Chimeric protein-protein
conjugates provide platforms for immunotherapy, targeted drug delivery, and
vaccine development. However, many desirable constructs cannot be produced through
direct expression, and the targeted coupling of two proteins is chemically
challenging. Here we present a new approach for the rapid and site-specific coupling
of proteins using native amino acids. Tyrosinase oxidizes exposed tyrosine
residues on polypeptides, generating ortho-quinones that react rapidly
with strategically placed cysteine residues in other proteins. This approach was
used to modify CRISPR-Cas9 and other substrates with small molecules, peptides
and even intact proteins. The conjugation of cell penetrating peptides to
CRISPR-Cas9 was shown to increase cellular genome editing efficiency by 20-fold
relative to unmodified Cas9. This technology represents a new paradigm for
biomolecular coupling, and paves the way to an unprecedented range of
multifunctional bioconjugates.
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