Methods for Preparation and Use of BacPROTACs for Targeted Protein Degradation in Mycobacteria and Other Bacteria
AssigneeWashington University
InventorsTimothy Wencewicz, Emily Williford, Helen Blaine, Christina Stallings
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Abstract
Among the various aspects of the present disclosure is the provision of bivalent agents for targeted protein degradation. Also disclosed are compositions including the bivalent agents and methods of use, including methods of reducing antibiotic resistance associated with an antibiotic-resistant bacterial infection and methods of treating an antibiotic-resistant bacterial infection.
Claims20
A composition for degradation of a targeted enzyme, the composition comprising a bivalent agent, the bivalent agent comprising:
- a. a targeted enzyme binding moiety configured to selectively bind to the targeted enzyme;
- b. a proteasome targeting moiety configured to selectively bind to a peptidase component of a proteosome;
- and
- c. a linker moiety, wherein the targeted protein binding moiety and protein degradation moiety are covalently linked at opposite ends of the linker moiety.
A method of reducing antibiotic resistance associated with an antibiotic-resistant bacterial infection in a subject, the method comprising administering a therapeutically effective amount of a composition comprising a bivalent agent to the subject, wherein the bivalent agent comprises a targeted enzyme binding moiety comprising anhydrotetracycline (aTC) and a proteasome targeting moiety comprising (S,E)-(3,5 difluorophenyl-2-)hept-2-eneamido)propanoic acid (DFP) attached at opposite ends of a polyethylene glycol (PEG) linker.
A method of treating an antibiotic-resistant bacterial infection in a subject, the method comprising administering a therapeutically effective amount of a composition comprising a bivalent agent to the subject, wherein the bivalent agent comprises a targeted enzyme binding moiety comprising anhydrotetracycline (aTC) and a proteasome targeting moiety comprising (S,E)-(3,5 difluorophenyl-2-)hept-2-eneamido)propanoic acid (DFP) attached at opposite ends of a polyethylene glycol (PEG) linker.
Dependencies are inferred from the claim text.