In addition, the hypervalent iodine handle displayed high reactivity for cross-coupling reactions under mild conditions. Our group previously reported a Suzuki-Miyaura cross-coupling of the hypervalent iodine bond of S-VBX with boronic acids in aqueous media. Under similar conditions, labelled AFYA-NH2 tetramer 3a was successfully coupled with boronic acid 14a in 54% isolated yield (Scheme 5b). Coupling of p-methoxyphenyl boronic acid (14a) was also successful with β-casomorphin peptide (1r) using a one-pot two-step procedure. A fluoresceinsubstituted boronic acid 14b also reacted with the in-situ generated O-VBX 3r, but a higher loading of palladium was required, as well as a higher ratio of DMSO to allow solubilization of the coupling partner. Finally, both reactive handles were successfully employed in a labeling/Suzuki-Miyaura/SPAAC one-pot three-step process to afford doubly-functionalized β-casomorphin peptide 17. A biotin unit was installed using the palladium catalyzed reaction on the hypervalent iodine moiety, whereas the PEG unit was introduced by the click reaction. Application to the thiol-mediated cellular uptake of streptavidin