7NI3

CRYSTAL STRUCTURE OF NATIVE HUMAN MYELOPEROXIDASE IN COMPLEX WITH CPD 3

7NI3 の概要

• エントリーDOI: 10.2210/pdb7ni3/pdb
• 関連するPDBエントリー: 7NI1
• 分子名称: Myeloperoxidase, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, PROTOPORPHYRIN IX CONTAINING FE, ... (10 entities in total)
• 機能のキーワード: oxidoreductase, complex, inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 135122.71

構造登録者

Sjogren, T.,Inghardt, T. (登録日: 2021-02-11, 公開日: 2022-02-23, 最終更新日: 2024-11-20)

主引用文献

Inghardt, T.,Antonsson, T.,Ericsson, C.,Hovdal, D.,Johannesson, P.,Johansson, C.,Jurva, U.,Kajanus, J.,Kull, B.,Michaelsson, E.,Pettersen, A.,Sjogren, T.,Sorensen, H.,Westerlund, K.,Lindstedt, E.L.
Discovery of AZD4831, a Mechanism-Based Irreversible Inhibitor of Myeloperoxidase, As a Potential Treatment for Heart Failure with Preserved Ejection Fraction.
J.Med.Chem., 65:11485-11496, 2022

PubMed Abstract: Myeloperoxidase is a promising therapeutic target for treatment of patients suffering from heart failure with preserved ejection fraction (HFpEF). We aimed to discover a covalent myeloperoxidase inhibitor with high selectivity for myeloperoxidase over thyroid peroxidase, limited penetration of the blood-brain barrier, and pharmacokinetics suitable for once-daily oral administration at low dose. Structure-activity relationship, biophysical, and structural studies led to prioritization of four compounds for in-depth safety and pharmacokinetic studies in animal models. One compound (AZD4831) progressed to clinical studies on grounds of high potency (IC, 1.5 nM ) and selectivity (>450-fold thyroid peroxidase ), the mechanism of irreversible inhibition, and the safety profile. Following phase 1 studies in healthy volunteers and a phase 2a study in patients with HFpEF, a phase 2/3 efficacy study of AZD4831 in patients with HFpEF started in 2021.

PubMed: 36005476
DOI: 10.1021/acs.jmedchem.1c02141

実験手法

X-RAY DIFFRACTION (2.1 Å)