Small-molecule inhibitors of cyclophilin D as potential therapeutics in mitochondria-related diseases

被引：23

作者：

Haleckova, Annamaria ^{[1
]}

Benek, Ondrej ^{[1
,2
]}

Zemanova, Lucie ^{[1
]}

Dolezal, Rafael ^{[1
,2
]}

Musilek, Kamil ^{[1
]}

机构：

[1] Univ Hradec Kralove, Dept Chem, Fac Sci, Rokitanskeho 62, Hradec Kralove 50003, Czech Republic

[2] Univ Hosp Hradec Kralove, Biomed Res Ctr, Hradec Kralove, Czech Republic

来源：

MEDICINAL RESEARCH REVIEWS | 2022年 / 42卷 / 05期

关键词：

cyclophilin D; drug discovery; enzyme inhibition; mitochondria; mitochondrial permeability transition pore; PERMEABILITY TRANSITION PORE; ISCHEMIA-REPERFUSION INJURY; STRUCTURE-BASED DESIGN; ATP SYNTHASE; SIGNAL-TRANSDUCTION; CYCLOSPORINE-A; DISCOVERY; ISOMERASE; IDENTIFICATION; DERIVATIVES;

D O I：

10.1002/med.21892

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Cyclophilin D (CypD) is a key regulator of mitochondrial permeability transition pore (mPTP) opening. This pathophysiological phenomenon is associated with the development of several human diseases, including ischemia-reperfusion injury and neurodegeneration. Blocking mPTP opening through CypD inhibition could be a novel and promising therapeutic approach for these conditions. While numerous CypD inhibitors have been discovered to date, none have been introduced into clinical practice, mostly owing to their high toxicity, unfavorable pharmacokinetics, and low selectivity for CypD over other cyclophilins. This review summarizes current knowledge of CypD inhibitors, with a particular focus on small-molecule compounds with regard to their in vitro activity, their selectivity for CypD, and their binding mode within the enzyme's active site. Finally, approaches for improving the molecular design of CypD inhibitors are discussed.

引用

页码：1822 / 1855

页数：34

共 104 条

[41] Structure-based design, synthesis, and biological evaluation of novel inhibitors of human cyclophilin A [J].