A pharmacological modality to sequester homomeric proteins.

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Protein-protein interactions are crucial but often require accessory proteins like E3 ligases.
• Existing methods can be limited by scope or lead to drug resistance.
• Homomeric proteins, prevalent in cells, present a potential target for novel therapeutic strategies.

Purpose of the Study:

• To develop a novel strategy for modulating protein function that does not rely on accessory proteins.
• To exploit the inherent symmetry of homomeric proteins as a vulnerability.
• To introduce polymerization-inducing chimeras (PINCHs) as a new class of bifunctional molecules.

Main Methods:

• Designing bifunctional molecules (PINCHs) composed of two linked ligands to bridge homomeric proteins.
• Utilizing protein symmetry to induce supramolecular assembly into insoluble polymers.
• Testing PINCH efficacy in cellular models, including targeting Keap1 and BCL6.

Main Results:

• Successfully designed PINCHs that efficiently polymerize four distinct target homomeric proteins.
• Demonstrated that a PINCH targeting Keap1 has a prolonged duration of action in cells.
• Observed selective reduction in B cell viability using a PINCH targeting BCL6.

Conclusions:

• PINCHs represent a novel and broadly applicable strategy for protein function modulation and knockout.
• Exploiting protein symmetry offers a unique approach to drug design, bypassing the need for accessory proteins.
• This method holds promise for developing new therapeutics with improved specificity and reduced resistance.