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One step N-terminal tagging of endogenous proteins for therapeutic delivery, diagnostics, and in vivo imaging

N-Terminal protein modification using adenosine substrates and aminoacyl transferase

Problem: 

The conjugation of synthetic molecules to the termini of proteins with minimal effects on protein folding and function is an active area of biochemical research. Previous N-terminal protein modification methods suffer from side reaction products, incomplete specificity, low yields, and harsh organic solvent conditions.

Solution: 

Researchers in the Petersson Lab have developed a minimal system for N-terminal protein labeling that uses an adenosine substrate of natural or unnatural amino acids and a single, readily available enzyme, aminoacyl tRNA transferase (AaT) from E. coli. 

The use of aminoacyl adenosyl donors increases the substrate scope and reaction scale for N-terminal protein modification. This process gives high yields of modified proteins under nondenaturing conditions to maintain natural protein folding and activity, while requiring only a single basic amino acid for specific recognition. Furthermore, the reaction can be scaled to large quantities of protein because there is no reliance on purified tRNA as with fully enzymatic modification methods.

Advantages: 

  • Easily carry out N-terminal protein modification under conditions that maintain protein folding
  • Adenosine substrate readily synthesized from commercially available materials
  • No prior protein manipulation required, proteins can be obtained from any source
  • High yields, reaction can be driven to completion
  • Not limited by substrate specificity of aminoacyl tRNA synthetase

Applications: 

  • Reduce barriers to therapeutic and diagnostic uses of modified proteins
  • Deliver therapeutically active proteins
  • Immobilize proteins on surfaces
  • Modify proteins with chromophores or fluorophores for in vitro sensors
  • Tag proteins with in vivo imaging agents

Transferase-mediated N-terminal protein modification

Stage of Development: 

Proof-of-concept

Intellectual Property: 

USSN 9,376,700 

Reference Media: 

Desired Partnerships: 

  • License
  • Co-development

Patent Information:

Inventors:

E. James Petersson
Alan Saghatelian

Docket # X5991 

For Information, Contact:

Cortney Cavanaugh
Licensing Officer, SEAS/SAS Licensing Group
University of Pennsylvania
215-898-9591
ccav5@upenn.edu

Keywords: