86807-94-5Relevant academic research and scientific papers
Exploring the Sn binding pockets in gingipains by newly developed inhibitors: Structure-based design, chemistry, and activity
Bialas, Arkadiusz,Grembecka, Jolanta,Krowarsch, Daniel,Otlewski, Jacek,Potempa, Jan,Mucha, Artur
, p. 1744 - 1753 (2007/10/03)
Arg-gingipains (Rgps) and Lys-gingipain (Kgp) are cysteine proteinases secreted by Porphyromonas gingivalis, the major pathogen implicated in periodontal disease. Gingipains are essential to the bacterium for its virulence and survival, and development of inhibitors targeting these proteins provides an approach to treat periodontal diseases. Here, we present the first example of structure-based design of gingipains inhibitors, with the use of the crystal structure of RgpB and the homology model of Kgp. Chloromethyl ketones were selected as suitable compounds to explore the specificity of the Sn binding region of both enzymes. Three series of inhibitors bearing Arg or Lys at P1 and different substituents at P2 and P3 were designed, synthesized, and tested. High potency (kobs/[I] ～ 107 M-1 s -1) was achieved for small ligands, such as the dipeptide analogues. The detailed analysis of Sn binding pockets revealed the molecular basis of inhibitory affinity and provided insight into the structure-activity relationship.
Potent bivalent thrombin inhibitors: Replacement of the scissile peptide bond at P1-P1' with arginyl ketomethylene isosteres
Steinmetzer, Torsten,Zhu, Bing Yan,Konishi, Yasuo
, p. 3109 - 3115 (2007/10/03)
We have designed highly potent synthetic bivalent thrombin inhibitors, which consist of an active site blocking segment, a fibrinogen recognition exosite blocking segment, and a linker connecting these segments. The bivalent inhibitors bind to the active
Tripeptidyl pyridinium methyl ketones as potent active site inhibitors of thrombin
Steinmetzer, Torsten,Konishi, Yasuo
, p. 1677 - 1682 (2007/10/03)
Several substituted methyl ketone derivatives of tripeptides with a C-terminal arginyl residue were synthesized as active site inhibitors of human α-thrombin. The most active compound among this series was the pyridinium methyl ketone D-Cha-Pro-Arg-PMK, w
