Targeting neurodegeneration and inflammation with thioredoxin-mimetic peptides.

Neurodegenerative and degenerative disorders are in part, driven by imbalances in cellular inflammatory and oxidation-reduction (redox) states. This vulnerability triggers the activation of highly selective and tightly regulated cellular defense networks against oxidative stress (OS), primarily involving the glutathione (GSH) and the thioredoxin (Trx) enzymatic complexes. These systems operate through reversible oxidation/reduction reactions involving the thiol groups of cysteine (Cys) residues, maintaining redox homeostasis and protecting cells from oxidative damage. To reinforce this defense under pathological conditions, a family of thioredoxin-mimetic (TXM) tri- and tetra-peptides was developed, based on the redox-active sequence motif of thioredoxin. These low-molecular-weight amino peptides each bearing two thiol groups, serve as a versatile platform of diverse redox-active molecules. Structurally optimized with blocked N- and C-termini, the TXM peptides exhibit enhanced cell permeability and are capable of crossing the blood-brain-barrier (BBB), thereby enabling therapeutic protection in both systemic degenerative and neurodegenerative disorders. Upon cellular entry, TXM peptides may undergo hydrolysis, potentially generating a cluster of 10-15 Cys-containing fragments including Cys, a precursor of GSH, which could further enhance and prolong their redox activity. This review summarizes key findings on the functional activity of various TXM-peptides, as demonstrated in both in vitro and in vivo models. Particular emphasis is given to TXM-CB3, which has shown protective effects across a wide range of animal models, including those of asthma, mild traumatic brain injury, obesity, viral infection, epilepsy, wound healing, myocardial infarction, aging, and inflammatory bowel-disease. These findings highlight the therapeutic potential of TXM-peptides in protecting cellular function under diverse pathological conditions.