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热休克蛋白90抑制与多靶点方法以最大化缺血性损伤中的心脏保护作用

Heat shock protein 90 inhibition and multi-target approach to maximize cardioprotection in ischaemic injury.

作者信息

Der Sarkissian Shant, Aceros Henry, Williams Pierre-Marc, Scalabrini Catherine, Borie Mélanie, Noiseux Nicolas

机构信息

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada.

Faculty of Medicine, Department of Surgery, Université de Montréal, Montréal, Québec, Canada.

出版信息

Br J Pharmacol. 2020 Aug;177(15):3378-3388. doi: 10.1111/bph.15075. Epub 2020 May 23.

Abstract

Despite several advances in medicine, ischaemic heart disease remains a major cause of morbidity and mortality. The unravelling of molecular mechanisms underlying disease pathophysiology has revealed targets for pharmacological interventions. However, transfer of these pharmcological possibilities to clinical use has been disappointing. Considering the complexity of ischaemic disease at the cellular and molecular levels, an equally multifaceted treatment approach may be envisioned. The pharmacological principle of 'one target, one key' may fall short in such contexts, and optimal treatment may involve one or many agents directed against complementary targets. Here, we introduce a 'multi-target approach to cardioprotection' and propose heat shock protein 90 (HSP90) as a target of interest. We report on a member of a distinct class of HSP90 inhibitor possessing pleiotropic activity, which we found to exhibit potent infarct-sparing effects.

摘要

尽管医学取得了多项进展,但缺血性心脏病仍然是发病和死亡的主要原因。对疾病病理生理学潜在分子机制的揭示为药物干预提供了靶点。然而,将这些药理学可能性转化为临床应用却令人失望。考虑到缺血性疾病在细胞和分子水平上的复杂性,可以设想一种同样多方面的治疗方法。在这种情况下,“一个靶点,一把钥匙”的药理学原则可能不够用,最佳治疗可能涉及一种或多种针对互补靶点的药物。在此,我们引入“心脏保护的多靶点方法”,并提出热休克蛋白90(HSP90)作为一个感兴趣的靶点。我们报告了一类具有多效活性的独特HSP90抑制剂的一个成员,我们发现它具有强大的梗死保护作用。

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