Noncovalent inhibition of the serine proteases, alpha-chymotrypsin and trypsin by trifluoro(organo)borates.
A series of potassium organotrifluoroborates were synthesized. Their stability to hydrolysis was determined in D2O, TRIS and phosphate buffer. It was found that in both D2O and TRIS buffers, these compounds are quite stable, whereas in phosphate buffer rapid hydrolysis occurs. Based on these results, a study was undertaken to determine whether potassium organotrifluoroborates can serve as protease inhibitors. It was found that potassium organotrifluoroborates increased inhibition by at least an order of magnitude over the corresponding boronates. Dixon plots showed that these compounds are reversible competitive inhibitors of alpha-chymotrypsin and trypsin. Based on 19F NMR, we speculate that they inactivate the enzymes as a result of the formation of hydrogen-bonds between fluorine atoms of the inhibitors and the serine protease.
Smoum
Reem
R
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, POB 12065, 91120, Jerusalem, Israel.
Rubinstein
Abraham
A
Srebnik
Morris
M
D001665:Binding Sites; D001667:Binding, Competitive; D001881:Borates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002918:Chymotrypsin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D001881:Borates; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D005461:Fluorine; D012697:Serine Endopeptidases; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D014357:Trypsin