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Pharmacological research

Pharmacological research

IF: 9.1
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Deoxyhypusine hydroxylase as a novel pharmacological target for ischemic stroke via inducing a unique post-translational hypusination modification

Published:1 February 2022 DOI: 10.1016/j.phrs.2021.106046 PMID: 35007708
Qiang Guo , Yi-Chi Zhang , Wei Wang , Yu-Qi Wang , Yang Liu , Zhuo Yang , Mei-Mei Zhao , Na Feng , Yan-Hang Wang , Xiao-Wen Zhang , Heng Yang , Ting-Ting Liu , Lun-Yong Shi , Xiao-Meng Shi , Dan Liu , Peng-Fei Tu , Ke-Wu Zeng

Abstract

Ischemic stroke remains one of the leading causes of death worldwide, thereby highlighting the urgent necessary to identify new therapeutic targets. Deoxyhypusine hydroxylase (DOHH) is a fundamental enzyme catalyzing a unique posttranslational hypusination modification of eukaryotic translation initiation factor 5A (eIF5A) and is highly involved in the progression of several human diseases, including HIV-1 infection, cancer, malaria, and diabetes. However, the potential therapeutic role of pharmacological regulation of DOHH in ischemic stroke is still poorly understood. Our study first discovered a natural small-molecule brazilin (BZ) with an obvious neuroprotective effect against oxygen-glucose deprivation/reperfusion insult. Then, DOHH was identified as a crucial cellular target of BZ using HuProt? human proteome microarray. By selectively binding to the Cys232 residue, BZ induced a previously undisclosed allosteric effect to significantly increase DOHH catalytic activity. Furthermore, BZ-mediated DOHH activation amplified mitophagy for mitochondrial function and morphology maintenance via DOHH/eIF5A hypusination signaling pathway, thereby protecting against ischemic neuronal injury in vitro and in vivo. Collectively, our study first identified DOHH as a previously unreported therapeutic target for ischemic stroke, and provided a future drug design direction for DOHH allosteric activators using BZ as a novel molecular template.

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Materials
Procduct Name CAS Molecular Formula Supplier Price
3-(2,4-Dichloro-5-methoxyphenyl)-2,3-dihydro-2-thioxo-4(1H)-quinazolinone 338967-87-6 C15H10Cl2N2O2S 210 suppliers $12.00-$1200.00
3-(2,4-Dichloro-5-methoxyphenyl)-2,3-dihydro-2-thioxo-4(1H)-quinazolinone 338967-87-6 C15H10Cl2N2O2S 210 suppliers $12.00-$1200.00
3-(2,4-Dichloro-5-methoxyphenyl)-2,3-dihydro-2-thioxo-4(1H)-quinazolinone 338967-87-6 C15H10Cl2N2O2S 210 suppliers $12.00-$1200.00
3-(2,4-Dichloro-5-methoxyphenyl)-2,3-dihydro-2-thioxo-4(1H)-quinazolinone 338967-87-6 C15H10Cl2N2O2S 210 suppliers $12.00-$1200.00

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