A team led by principal investigators Bobo Dang and Ting Zhou at Westlake University/Westlake Laboratory have developed a high-throughput platform for engineering fast-acting covalent protein therapeutics. Their study, titled “A high-throughput selection system for fast-acting covalent protein drugs” published in Science, opens new avenues for next-generation biologics.

Covalent small-molecule drugs have shown great success in cancer therapy by forming irreversible bonds with their targets. This has inspired efforts to extend covalent strategies to protein therapeutics, especially engineered miniproteins. However, their development is limited by a kinetic mismatch: Miniproteins are rapidly cleared in vivo, whereas covalent bond formation is typically slow. In addition, high-throughput platforms for systematically optimizing covalent protein reactivity have been lacking.

To address this challenge, the researchers proposed that precise spatial positioning of chemical warheads within protein scaffolds could enable molecular preorganization, thereby accelerating covalent bond formation without increasing intrinsic reactivity.