טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMeital Netz
SubjectAGEs' inhibition by AGEs-breakers
DepartmentDepartment of Biotechnology and Food Engineering
Supervisors Full Professor Shoham Yuval
Mr. Neeman Ishak (Deceased)
Mr. Werman Moshe


Abstract

Glycation is a spontaneous reaction between reducing sugars such as glucose and proteins, initiated by non-enzymatic interaction of glucose-carbonyl groups with the protein-amino groups. The late products of the glycation reaction are heterogeneous adducts known as advanced glycation endproducts (AGEs).  The toxic effects of AGEs result from structural and functional alterations in proteins, especially from crosslinking of proteins. These changes are associated to the normal aging process and to several pathological conditions such as diabetes complications. Potential therapeutic drugs capable of inhibiting AGEs formation and/or breaking the already existing AGEs-protein crosslinks are subject of intense research.

ALT711, a Thiazolium based AGEs-breaker, capable of breaking the glucose derived crosslinks and has the potential to reverse damage related to aging and diabetes,

was  reported to be effective in vitro and in several animal studies. In the present study we evaluated the ability of a new derivative of ALT711, AG2413, to inhibit AGEs formation and to break pre-formed crosslinks. The degree of activity of this compound was evaluated in several in vitro protein systems and in an induced diabetes animal model. The activity of AG2413 as AGEs’ inhibitor, in vitro, measured by AGEs’ specific fluorescence and fructosamine concentration, was significantly higher then the activity of ALT711. The compound ability to break crosslinks between AGEs and collagen, in vitro, was also higher then the activity of ALT711. In the animal model, AG2413 showed better ability to inhibit glycation of hemoglobin and collagen, and slightly lower to inhibit lens crystalin glycation, as compered to ALT711. The results of this study indicate that AG2413 is a potential therapeutic agent against the different complication associated with AGEs in diabetes and aging.