Synthesis And Evaluation Of A Novel Inhibitor Of Glutaminyl Cyclase

Glutaminyl cyclase(QC)could catalyze the N-terminal glutamine and glutamate of peptide or proteins to formation pyroglutamic acid(p Glu),which plays an important role in the process of the p Glu’s mature and functionalization.Recently studies have shown that QC could catalyze amyloid beta peptide N-terminal glutamine to react to form p E-A β defined as a class of more neuron-active cyclic compound,which promotes AD.It’s also known that high specific expression of QC is a character of AD in the early pathological changes.As a consequence of all the above factors,efficient QC inhibitors are expected to become a new direction for anti-AD drug development.In this paper,the article main research content include:(1)Based on h QC crystal structure,we have designed and synthesized of 53 LBQI series of compounds.All of those derivatives have been defined with data representation of1H-NMR、13C-NMR and HR-MS.(2)By molecular cloning,expressing,purification and other molecular biology techniques,a highly active recombinant pituitary glutaminyl cyclase(QC)has been obtained.(3)Using GD-QC test system for the enzyme-linked inhibitor screening model,the 53 compounds was evaluated,selected a group of highly active competitive inhibitors of QC.Further SAR analysis showed that,the arrangement of the electron cloud of an imidazole ring and the length of a flexible chain could significantly affected the inhibitory activity of the compound.The introduction of benzene ring structure of the aromatic domain can improve QC inhibitory activity of compounds.(4)Competitive inhibitors’ activities in cells are evaluated with double transfer cell model.(5)the structure-activity relationship of inhibitors and the property of the binding site of enzyme have been researched with attempts by SPR、ITC and UV-visible absorption spectroscopy.In vitro compounds and protein analysis,LBQIserial compounds belong to reversible inhibitiors of QC,and the conjugation ratio is 1:1.The above findings confirmed that,LBQI series of compounds were designed and synthesized in this paper at the molecular and cellular level showed significant inhibition of QC activity,is a kind of new,reversible competitive inhibitors of QC.The study in the validation of the initial vision of the subject,as the QC inhibitor class innovative anti AD drug research and development provides an important support.