Photosensitized Oxidative Dimerization at Tyrosine by a Water‐Soluble 4‐Amino‐1,8‐naphthalimide

Abstract

The oxidation of proteins generates reactive amino acid (AA) residue intermediates, leading to protein modification and cross-linking. Aerobic studies with peptides and photosensitizers allow for the controlled generation of reactive oxygen species (ROS) and reactive AA residue intermediates, providing mechanistic insights as to how natural protein modifications form. Such studies have inspired the development of abiotic methods for protein modification and crosslinking, including applications of biomedical importance. Dityrosine linkages derived from oxidation at tyrosine (Tyr) residues represent one of the more well-understood oxidation-induced modifications.Here we demonstrate an aerobic, visible light-dependent oxidation reaction of Tyr-containing substrates promoted by a water-soluble 4-amino-1,8-naphthalimide-based photosensitizer. The developed procedure converts Tyr-containing substrates into o,o'-Tyr-Tyr linked dimers. The regioselectively formed o,o'-Tyr-Tyr linkage is consistent with dimeric standards prepared using a known enzymatic method. A crossover study with two peptides provides a statistical mixture of three distinct o,o'-Tyr-Tyr linked dimers, supporting a mechanism that involves Tyr residue oxidation followed by intermolecular combination. BackgroundRecently, Kelly and coworkers delineated the solvent-dependent photophysical properties of 4-amino-1,8-naphthalene [a] E.

Creating a Natural Vascular Scaffold by Photochemical Treatment of the Extracellular Matrix for Vascular Applications

“…It is this crosslinking of amino acid residues in the ECM proteins of an artery that creates the NVS effect. Exploration of the 10-8-10 Dimer and light dose range ( Figure 5 ) capable of eliciting this crosslinking effect measured by dityrosine formation in a simple experimental system is a continuation of the study by Keyes and colleagues [ 10 ] to understand the reaction kinetics of the formation of amino acid crosslinking.…”

“…Photoactivation of 10-8-10 Dimer results in the formation of excited species that can initiate inter and intra formation of covalent bonds in proteins. A series of experiments were conducted previously by Keyes et al [ 10 ], wherein a photochemical mechanism was proposed. The proposed mechanism results in covalent bond formation within and between proteins when exposed to the 10-8-10 Dimer in the presence of light at its absorption maximum.…”

“…Decreasing the rate of restenosis should translate to higher long-term primary patency rates, and therefore, better patient mobility, reduced pain and improved quality of life. Systematic experiments were conducted to understand the photochemical mechanism of action of 10-8-10 Dimer when exposed to light at its absorption maximum [ 10 , 15 ]. These experiments support that the 4-amino substituted 1,8-naphthalimide core of the 10-8-10 Dimer undergoes photoexcitation upon illumination by a 450 nm light to generate a transient, reversible, excited state of the molecule ( Figure 2 and Figure 3 ).…”

“…While the photoactivated 10-8-10 Dimer catalyzed covalent bond formation between oxidizable amino acids fits into the category of molecular crosslinking [ 10 ], it is important to distinguish this reaction from the crosslinking of tissues as a result of chemical crosslinkers for tissue fixation [ 11 ], the pathological crosslink formation in atherosclerotic arteries as a result of decades-long exposure to oxidants [ 12 ] and from other therapies based on similar mechanisms but exposing mostly decellularized tissues for prolonged photoactivated treatment [ 13 ]. The actual mechanisms of photochemical protein crosslinking are not easily identified because of the wide variety of possible reactive species and conformations found in proteins.…”

Chemoselective, oxidation-induced macrocyclization of tyrosine-containing peptides

“…While these biaryl linkages are frequently identified as clinical markers of oxidative stress and aging, they have been shown to impart beneficial structural stability and elasticity to peptide and protein-based systems. [14][15][16] Similar transformations are commonly observed in natural product biosynthesis pathways, resulting in structurally constrained monoand polycyclic peptides with promising and diverse biological activities. 17 Exemplary biaryl-linked cyclic peptides that derive from phenolic-residue oxidation include the angiotensin-converting enzyme inhibitor, K-13 1 (C-O-linked), myxarylin 2 (C-N-linked), and C-Clinked antimicrobial peptides such as arylomycin A2 3 (Figure 1A).…”