A high-throughput selection system for fast-acting covalent protein drugs
Summary
Covalent protein drugs offer therapeutic potential but are limited by slow target engagement and the absence of high-throughput selection platforms. Rapid covalent binding requires coordinated optimization of affinity, stability, and warhead geometry-an intrinsically multidimensional challenge. We develop a yeast display platform coupled with chemoselective modification that enables selection of fast-acting covalent proteins without increasing intrinsic warhead reactivity. Using this syste
Content
# A high-throughput selection system for fast-acting covalent protein drugs
*Published: 2026 Apr 2*
Covalent protein drugs offer therapeutic potential but are limited by slow
target engagement and the absence of high-throughput selection platforms. Rapid
covalent binding requires coordinated optimization of affinity, stability, and
warhead geometry-an intrinsically multidimensional challenge. We develop a yeast
display platform coupled with chemoselective modification that enables selection
of fast-acting covalent proteins without increasing intrinsic warhead
reactivity. Using this system, we engineered a covalent programmed death-ligand
1 (PD-L1) antagonistic nanobody with rapid crosslinking kinetics (kobs = 0.18
min-1, t1/2 = 3.8 min) and improved tumor suppression compared with envafolimab
and atezolizumab. Similarly, we engineered a fast-acting covalent interleukin-18
(IL-18) (kobs = 0.54 min-1, t1/2 = 1.3 min) and a covalent miniprotein targeting
the receptor binding domain (RBD) of SARS-CoV-2, demonstrating applicability
across protein modalities.
DOI: 10.1126/science.adv3081