Advanced glycation end products (AGEs) are involved in age-related diseases, including the complications of diabetes and chronic renal impairment with arterial stiffening.
Alagebrium chloride (ALT-711) is an AGE-lowering agent with beneficial effects in renal structural and functional parameters in diabetes, decreased diabetes-accelerated
atherosclerosis, and age-related myocardial stiffening.
ALT-711 exhibits a structural homology to
thiamine, and it was suggested to interfere with
thiamine metabolism.
Thiamine is converted to
thiamine diphosphate (TDP) by
thiamine diphosphokinase (TDPK). TDP is a cofactor for
pyruvate dehydrogenase, α-ketoglutarate
dehydrogenase and
transketolase. A decreased activity of these
enzymes due to TDP deficiency results in disorders such as
beriberi and
Wernicke-Korsakoff syndrome. Therefore, we investigated whether
ALT-711 is an inhibitor of TDPK. Molecular modeling studies showed that
ALT-711 fits into the
thiamine-binding pocket of TDPK, and there are three interactions between the thiazolium ring and the
enzyme, as well as parallel stacking between the phenyl ring and the
indole ring of Trp222B.
Enzyme kinetic experiments also showed that
ALT-711 dose-dependently decreased TDPK activity with K(i)s, calculated by different experiments and fitting models ranging from 0.88 to 1.09 mM. Fitting of the kinetic data favored mixed-mode inhibition with a major role for competitive inhibition. In summary, our results suggest that
ALT-711 is a low-affinity inhibitor of TDPK, but is unlikely to interfere with
thiamine metabolism at therapeutic concentrations. However, when new AGE-crosslink breakers based on
thiamine are designed, care should be taken that they do not act as more potent competitive inhibitors than
ALT-711.