témavezető: Somsák László
helyszín (magyar oldal): DE Kémia épület E 422 helyszín rövidítés: E 422
A kutatási téma leírása:
Carbohydrates play pivotal roles in living organisms. In mono-, oligo-, and polymeric forms they are long known nutrients and components of skeletal and connective tissues. Mono- and oligosaccharides function as general mediators of recognition processes and signaling. In the latter cases interactions with proteins (lectins, glycoenzymes) are crucial. To understand this complex biological interplay from the carbohydrate side, extensive synthetic work is necessary to produce the natural saccharides in sufficient quantities to study the biological actions. On the other hand, a wide variety of glycomimetics is also needed for modulating the carbohydrate-protein interactions to decipher the biological functions and for possible therapeutic uses.
The post-translational modification of proteins by attaching N-acetyl-D-glucosamine (O-GlcNAc) by a β-glycosidic linkage onto serine and threonine OH-groups has been proven to be complementary to, competitive with, and as frequent as phosphorylation. Two enzymes are responsible for the addition and removal of the O-GlcNAc modification: uridine diphospho-N-acetylglucosamine:polypeptide β-N-acetylglucosaminyltransferase (OGT) and a special β-N-acetyl-glucosaminidase known as O-GlcNAcase (OGA), respectively. This monoglycosylation plays a role in most of the fundamental cellular processes such as transcription, translation, cell signaling, cell trafficking, cell cycle control and development, and is considered as a general nutrient and stress sensor. Its disregulation is linked to cardiovascular disorders, type 2 diabetes, erectile disfunction, retinopathy and Alzheimer's disease. Some heat shock proteins (stress proteins, chaperones) have been shown to be O-GlcNAc specific lectins which may exert their protein repairing function by elevated O-GlcNAcylation levels after cellular stress. Increasing O-GlcNAc levels by e. g. inhibition of OGA with small molecules may result in beneficial effects in the above diseased states.
Relatively few inhibitors of OGA are known to date, therefore there are grounds for the design and synthesis of new compounds and their enzyme kinetic evaluation. Recently we have identified new glucono-1,5-lactone hydrazone derivatives which proved efficient inhibitors of hOGA (Eur. J. Med. Chem. 2021, 223, 113649. Doi: 10.1016/j.ejmech.2021.113649; Int. J. Mol. Sci. 2022, 23, 1037. Doi: 10.3390/ijms23031037).
During the PhD research potential inhibitors of OGA will be designed and synthesized based on monosaccharide derivatives, and their effects on hOGA will be studied by biochemical methods. The research may result in new, potent inhibitors of the important human enzyme which may also have potential towards drug development. International collaborations in the field of enzyme kinetic evaluation of the inhibitors as well as understanding their mechanism of action by computational methods are foreseen with teams in United Kingdom and Czech Republic.
előírt nyelvtudás: angol felvehető hallgatók száma: 2
Jelentkezési határidő: 2023-01-16
2024. IV. 17. ODT ülés Az ODT következő ülésére 2024. június 14-én, pénteken 10.00 órakor kerül sor a Semmelweis Egyetem Szenátusi termében (Bp. Üllői út 26. I. emelet).
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