155369-11-2Relevant articles and documents
Discovery of Novel Nonpeptidic PAR2 Ligands
Gmeiner, Peter,Hübner, Harald,Kaindl, Jonas,Kl?sel, Ilona,Schmidt, Maximilian F.,Weikert, Dorothee
supporting information, p. 1316 - 1323 (2020/07/04)
Proteinase-activated receptor 2 (PAR2) is a class A G protein-coupled receptor whose activation has been associated with inflammatory diseases and cancer, thus representing a valuable therapeutic target. Pathophysiological roles of PAR2 are often characterized using peptidic PAR2 agonists. Peptidic ligands are frequently unstable in vivo and show poor bioavailability, and only a few approaches toward drug-like nonpeptidic PAR2 ligands have been described. The herein-described ligand 5a (IK187) is a nonpeptidic PAR2 agonist with submicromolar potency in a functional assay reflecting G protein activation. The ligand also showed substantial β-arrestin recruitment. The development of the compound was guided by the crystal structure of PAR2, when the C-terminal end of peptidic agonists was replaced by a small molecule based on a disubstituted phenylene scaffold. IK187 shows preferable metabolic stability and may serve as a lead compound for the development of nonpeptidic drugs addressing PAR2.
Design and synthesis of a biologically active antibody mimic based on an antibody-antigen crystal structure
Smythe,Von Itzstein
, p. 2725 - 2733 (2007/10/02)
We have used the crystal structure of an N9 sialidase (antigen)-NC41 (antibody) complex to design a low molecular weight compound that mimics the binding function of the macromolecular antibody. The components of recognition between the antibody and the protein antigen have been analyzed from the energy-refined crystal complex. From this analysis, four amino acid residues on the antibody binding surface, which make direct contact with the active-site loop 368-370 of the antigen, have been identified as contributing the majority of the binding energy of the protein. The designed target compound, a constrained cyclic peptide, which mimics the receptor-bound conformation of these amino acids, has been synthesized and found to inhibit N9 sialidase activity, with a K(i) of 1 x 10-4 M.
