Incorporation of a Highly Reactive Oxalyl Thioester-Based Interacting Handle into Proteins

[Image: see text] Providing biomolecules with extended physicochemical, biochemical, or biological properties is a contemporary challenge motivated by impactful benefits in life or materials sciences. In this study, we show that a latent and highly reactive oxalyl thioester precursor can be efficiently introduced as a pending functionality into a fully synthetic protein domain following a protection/late-stage deprotection strategy and can serve as an on-demand reactive handle. The approach is illustrated with the production of a 10 kDa ubiquitin Lys48 conjugate.