Abstract
GLUCOSE and other reducing sugars react with proteins by a non-enzymatic, post-translational modification process called non-enzymatic glycosylation or glycation. The sugar-derived carbonyl group adds to a free amine, forming a reversible adduct which over time rearranges to produce a class of products termed advanced-glycation end-products (AGEs). These remain irreversibly bound to macromolecules and can covalently crosslink proximate amino groups1,2. The formation of AGEs on long-lived connective tissue and matrix components accounts largely for the increase in collagen crosslinking that accompanies normal ageing and which occurs at an accelerated rate in diabetes3,4. AGEs can activate cellular receptors and initiate a variety of pathophysiological responses5–9. They modify an appreciable fraction of circulating low-density lipoproteins preventing uptake of these particles by their high-affinity tissue receptors10,11. Advanced glycation has also been implicated in the pathology of Alzheimer's disease12,13. Because AGEs may form by a pathway involving reactive α-dicarbonyl intermediates1,2,14, we investigated a potential pharmacological strategy for selectively cleaving the resultant glucose-derived protein crosslinks. We now describe a prototypic AGE crosslink 'breaker', N-phenacylthiazolium bromide (PTB), which reacts with and cleaves covalent, AGE-derived protein crosslinks. The ability of PTB to break AGE crosslinks in vivo points to the importance of an α-dicarbonyl intermediate in the advanced glycation pathway and offers a potential therapeutic approach for the removal of established AGE crosslinks.
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Vasan, S., Zhang, X., Zhang, X. et al. An agent cleaving glucose-derived protein crosslinks in vitro and in vivo. Nature 382, 275–278 (1996). https://doi.org/10.1038/382275a0
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DOI: https://doi.org/10.1038/382275a0
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