Glycation-mediated protein crosslinking and stiffening in mouse lenses are inhibited by carboxitin in vitro

• Published in: Glycoconjugate journal Vol. 38; no. 3; pp. 347 - 359
• Main Authors: Nandi, Sandip K., Rankenberg, Johanna, Rakete, Stefan, Nahomi, Rooban B., Glomb, Marcus A., Linetsky, Mikhail D., Nagaraj, Ram H.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.06.2021; Springer Nature B.V
• Subjects: Advanced glycosylation end products; Advances in Glcation: from food to human health and disease; Aging; Animals; Ascorbic acid; Biochemistry; Biomedical and Life Sciences; Carbonyl compounds; Cataracts; Cattle; Eye lens; Glutathione; Glutathione - analogs & derivatives; Glutathione - chemical synthesis; Glycation End Products, Advanced; Glycosylation; Lens, Crystalline - drug effects; Lens, Crystalline - physiology; Life Sciences; Mechanical stimuli; Mice; Mice, Inbred C57BL; Original Article; Oxidative stress; Pathology; Protein Binding; Proteins; Tetroses - metabolism; Tumor Cells, Cultured; Carboxitin; Aging; Presbyopia; Lens; Mass spectrometry; Glycation; Protein crosslinking
• ISSN: 0282-0080; 1573-4986; 1573-4986
• DOI: 10.1007/s10719-020-09961-9

Proteins in the eye lens have negligible turnover and therefore progressively accumulate chemical modifications during aging. Carbonyls and oxidative stresses, which are intricately linked to one another, predominantly drive such modifications. Oxidative stress leads to the loss of glutathione (GSH) and ascorbate degradation; this in turn leads to the formation of highly reactive dicarbonyl compounds that react with proteins to form advanced glycation end products (AGEs). The formation of AGEs leads to the crosslinking and aggregation of proteins contributing to lens aging and cataract formation. To inhibit AGE formation, we developed a disulfide compound linking GSH diester and mercaptoethylguanidine, and we named it carboxitin. Bovine lens organ cultured with carboxitin showed higher levels of GSH and mercaptoethylguanidine in the lens nucleus. Carboxitin inhibited erythrulose-mediated mouse lens protein crosslinking, AGE formation and the formation of 3-deoxythreosone, a major ascorbate-derived AGE precursor in the human lens. Carboxitin inhibited the glycation-mediated increase in stiffness in organ-cultured mouse lenses measured using compressive mechanical strain. Delivery of carboxitin into the lens increases GSH levels, traps dicarbonyl compounds and inhibits AGE formation. These properties of carboxitin could be exploited to develop a therapy against the formation of AGEs and the increase in stiffness that causes presbyopia in aging lenses.