An agent cleaving glucose-derived protein crosslinks in vitro and in vivo.
Glucose and other reducing sugars react with proteins by a nonenzymatic, post-translational modification process called nonenzymatic 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 groups. 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 diabetes. AGEs can activate cellular receptors and initiate a variety of pathophysiological responses. They modify an appreciable fraction of circulating low-density lipoproteins preventing uptake of these particles by their high-affinity tissue receptors. Advanced glycation has also been implicated in the pathology of Alzheimer's disease. Because AGEs may form by a pathway involving reactive alpha-dicarbonyl intermediates, 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 alpha-dicarbonyl intermediate in the advanced glycation pathway and offers a potential therapeutic approach for the removal of established AGE crosslinks.
Vasan
S
S
The Picower Institute for Medical Research, Manhasset, New York 11030, USA.
Zhang
X
X
Zhang
X
X
Kapurniotu
A
A
Bernhagen
J
J
Teichberg
S
S
Basgen
J
J
Wagle
D
D
Shih
D
D
Terlecky
I
I
Bucala
R
R
Cerami
A
A
Egan
J
J
Ulrich
P
P
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000648:ultrastructure; D000818:Animals; D003432:Cross-Linking Reagents / Q000378:metabolism; D003920:Diabetes Mellitus / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism*; D007074:Immunoglobulin G / Q000097:blood; D051381:Rats; D012709:Serum Albumin / Q000378:metabolism; D013844:Thiazoles / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; D007074:Immunoglobulin G; C101705:N-phenacylthiazolium bromide; D012709:Serum Albumin; D013844:Thiazoles; D005947:Glucose