To enable complete site selectivity, another strategy is usually followed: the installation of nonnatural functionalities into peptides and proteins, enabling "bioorthogonal" reactions proceeding exclusively at the modified site. The use of cycloadditions reactions, in particular between azides and alkynes, has been most often exploited in the past, but new types of bioorthogonal reactions proceeding with high rates under mild conditions, especially in absence of metal catalysts, are still urgently needed. Due to their unique reactivity, the introduction of HIRs into peptides and proteins appears highly attractive in this context (Fig ). Nevertheless, the modification of hypervalent iodine reagents without touching the highly reactive iodine center is difficult and has been achieved only on small organic molecules so far. The only successful approach was reported by our group in 2019 and 2022. Vinylbenziodoxolones (VBXs) products were formed through the addition of Cys/Tyr containing peptides/proteins to EBXs. The VBXs could undergo bioorthogonal Suzuki couplings to introduce aryl substituents onto peptides and proteins. However, high Pd catalyst loading and tedious optimizations are necessary for this cross-coupling, which therefore fails to meet the requirements for a "Click reaction". In fact, VBXs reagents are far less reactive than EBXs, and only a few transformations are possible, whereas hundreds of reactions under mild conditions are known for EBXs. If a method could be found to install EBXs onto peptides/proteins, this would therefore open the door to broad range of new bioorthogonal transformations. Herein, we show that a bifunctional EBX reagent, containing two electrophilic sites: the alkynyl benziodoxolone (BX) and an activated pentafluorophenyl (PFP) ester, can undergo selective amide bond formation on the N-terminus or a Lys side chain with the PFP ester, forming peptide-EBX reagents (Fig 1b). This transformation was possible both in solution and on solid phase, the later allowing straightforward purification. Using these reagents, two transformations proceeding in absence of a transition metal catalyst were investigated. First, fast and selective S-alkynylation and -alkenylation with Cys containing peptides and proteins were developed, a simple solvent switch allowing changing the outcome of the reaction (Fig ). These transformations could also be accomplished in one-pot, without purification of the EBX reagents. Second, a visible light mediated C-terminal decarboxylative alkynylation of peptides catalyzed by organic dyes was implemented. In absence of reaction partner, in the case the peptide bearing the EBX reagent had a free C-Terminus, a new type of macrocyclization occurred, resulting in unprecedented macrocycles incorporating the rigid alkyne unit. The method was used to develop new potential inhibitors of the Keap1-Nrf2 protein-protein interaction. The rigidity of the arylalkyne linker was important to achieve efficient binding to Keap1, as reduction of the triple bond led to a 5.5-fold decrease in binding affinity.