The concept of covalent drugs has been mostly disregarded for many years by the pharmaceutical industry for fear of side effects and toxicity in case of off-target effects. Nevertheless, several papers throughout the last years have heralded the beneficial properties of covalent drugs and it has been realized that covalent binding ligands represent attractive drug candidates in an era where drug resistance forms a fundamental problem. The main challenge in the design of such covalent ligands, resides in the design of the specific functional group or reactive ‘warhead’ which should engage in covalent bond formation with selected functionalities on the target proteins. While traditionally this has been achieved by targeting cysteines with moderately reactive electrophiles, we here propose the exploitation of the furan-oxidation technology, newly developed within OBCR that allows to target lysine residues. Though these are considerably more abundant than cysteines, selectivity is ensured by the use of a caged furan ‘warhead’. Only upon selective oxidation, achievable through the release of endogenous reactive oxygen species upon binding a membrane target receptor, will the warhead be triggered for reaction with a nucleophilic residue, provided this is located in close proximity. Furan-modified apelin peptides and anti-EGFR nanobodies will be designed and studied for their potential as next generation covalent drug leads.