Westlake University Engineers High-Throughput Platform for Fast-Acting Covalent Protein Drugs to Outpace In Vivo Clearance

New high-throughput platform from Westlake University engineers protein drugs that form permanent bonds with targets faster than they can be cleared from the body.

By: AXL Media

Published: Apr 3, 2026, 10:45 AM EDT

Source: Information for this report was sourced from Science

Solving the Kinetic Mismatch in Biologics

While covalent small-molecule drugs have revolutionized cancer therapy by forming permanent, irreversible bonds with their targets, translating this success to larger protein therapeutics has been historically difficult. The primary obstacle is a "kinetic mismatch": engineered miniproteins are often cleared from the body very quickly, while the formation of a covalent bond is typically a slow chemical process. To bridge this gap, Principal Investigators Bobo Dang and Ting Zhou at Westlake University proposed a new strategy of molecular preorganization. By precisely positioning chemical "warheads" within a protein scaffold, they aimed to accelerate bond formation without increasing the drug's intrinsic toxicity.

A High-Throughput Platform for Rapid Engineering

To identify the optimal configurations for these fast-acting proteins, the team built a high-throughput selection system that combines yeast surface display with chemoselective modification. This platform allows researchers to screen millions of protein variants and a wide array of crosslinkers simultaneously. By optimizing the local chemical environment around the warhead, the system identifies variants that can engage their targets almost instantly. This rapid engagement ensures that the drug locks onto its target before it can be filtered out by the kidneys or liver, solving the fundamental limitation of rapid in vivo clearance that has hampered previous miniprotein efforts.

Superior Antitumor Activity in PD-L1 Targeting

The team applied this platform to develop a covalent antagonist for the PD-L1 immune checkpoint, designated as IB101. Structural analysis confirmed that IB101 creates a specialized binding pocket that holds the chemical warhead in a highly reactive conformation. In mouse models, IB101 effectively blocked the PD-1/PD-L1 pathway, demonstrating stronger and more durable tumor suppression than traditional antibody-based therapies. Even though IB101 has a short half-life in the bloodstream, its ability to form a permanent bond upon contact allowed it to outperform conventional treatments that require a constant, high concentration to remain effective.