8G1W

Crystal Structure Matriptase (C731S) in Complex with Inhibitor VD4162B

8G1W の概要

• エントリーDOI: 10.2210/pdb8g1w/pdb
• 分子名称: Suppressor of tumorigenicity 14 protein, Cyclic peptide inhibitor (ACE)Y(DTR)(NLE)(THZ), Cyclic peptide inhibitor (ACE)Y(DTR)(NLE)(KCM), ... (5 entities in total)
• 機能のキーワード: matriptase, inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 28045.06

構造登録者

Lovell, S.,Kashipathy, M.M.,Battaile, K.P.,Janetka, J.W. (登録日: 2023-02-03, 公開日: 2024-02-07, 最終更新日: 2024-04-10)

主引用文献

Damalanka, V.C.,Banas, V.,De Bona, P.,Kashipathy, M.M.,Battaile, K.,Lovell, S.,Janetka, J.W.
Mechanism-Based Macrocyclic Inhibitors of Serine Proteases.
J.Med.Chem., 67:4833-4854, 2024

PubMed Abstract: Protease inhibitor drug discovery is challenged by the lack of cellular and oral permeability, selectivity, metabolic stability, and rapid clearance of peptides. Here, we describe the rational design, synthesis, and evaluation of peptidomimetic side-chain-cyclized macrocycles which we converted into covalent serine protease inhibitors with the addition of an electrophilic ketone warhead. We have identified potent and selective inhibitors of TMPRSS2, matriptase, hepsin, and HGFA and demonstrated their improved protease selectivity, metabolic stability, and pharmacokinetic (PK) properties. We obtained an X-ray crystal structure of phenyl ether-cyclized tripeptide VD4162 () bound to matriptase, revealing an unexpected binding conformation. Cyclic biphenyl ether VD5123 () displayed the best PK properties in mice with a half-life of 4.5 h and compound exposure beyond 24 h. These new cyclic tripeptide scaffolds can be used as easily modifiable templates providing a new strategy to overcoming the obstacles presented by linear acyclic peptides in protease inhibitor drug discovery.

PubMed: 38477709
DOI: 10.1021/acs.jmedchem.3c02388

実験手法

X-RAY DIFFRACTION (1.2 Å)