6IC7

Human cathepsin-C in complex with dipeptidyl cyclopropyl nitrile inhibitor 3

6IC7 の概要

• エントリーDOI: 10.2210/pdb6ic7/pdb
• 関連するPDBエントリー: 6IC5 6IC6
• 分子名称: Dipeptidyl peptidase 1, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (8 entities in total)
• 機能のキーワード: cathepsin-c, cysteine protease, structure-based drug design, arthritis, hydrolase
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 41296.59

構造登録者

Hakansson, M.,Logan, D.T.,Korkmaz, B.,Lesner, A.,Wysocka, M.,Gieldon, A.,Gauthier, F.,Jenne, D.,Lauritzen, C.,Pedersen, J. (登録日: 2018-12-02, 公開日: 2019-04-24, 最終更新日: 2024-11-13)

主引用文献

Korkmaz, B.,Lesner, A.,Wysocka, M.,Gieldon, A.,Hakansson, M.,Gauthier, F.,Logan, D.T.,Jenne, D.E.,Lauritzen, C.,Pedersen, J.
Structure-based design and in vivo anti-arthritic activity evaluation of a potent dipeptidyl cyclopropyl nitrile inhibitor of cathepsin C.
Biochem. Pharmacol., 164:349-367, 2019

PubMed Abstract: Cathepsin C (CatC) is a dipeptidyl-exopeptidase which activates neutrophil serine protease precursors (elastase, proteinase 3, cathepsin G and NSP4) by removing their N-terminal propeptide in bone marrow cells at the promyelocytic stage of neutrophil differentiation. The resulting active proteases are implicated in chronic inflammatory and autoimmune diseases. Hence, inhibition of CatC represents a therapeutic strategy to suppress excessive protease activities in various neutrophil mediated diseases. We designed and synthesized a series of dipeptidyl cyclopropyl nitrile compounds as putative CatC inhibitors. One compound, IcatC ((S)-2-amino-N-((1R,2R)-1-cyano-2-(4'-(4-methylpiperazin-1-ylsulfonyl)biphenyl-4-yl)cyclopropyl)butanamide)) was identified as a potent inhibitor of both human and rodent CatC. In mice, pharmacokinetic studies revealed that IcatC accumulated in the bone marrow reaching levels suitable for CatC inhibition. Subcutaneous administration of IcatC in a monoclonal anti-collagen antibody induced mouse model of rheumatoid arthritis resulted in statistically significant anti-arthritic activity with persistent decrease in arthritis scores and paw thickness.

PubMed: 30978322
DOI: 10.1016/j.bcp.2019.04.006

実験手法

X-RAY DIFFRACTION (2 Å)