脓毒症和严重SARS-CoV-2感染/新冠肺炎中靶向内溶酶体酸化和信号传导的小分子

M. Blaess, O. Sommerfeld, R. Csuk, H. Deigner
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引用次数: 0

摘要

脓毒症和严重急性呼吸综合征冠状病毒2(SARS-CoV-2)感染及其严重形式的2019冠状病毒病(新冠肺炎)是现代医学的主要挑战。治疗选择有限,大多是有症状的,部分依赖抗体和皮质类固醇,在严重急性呼吸系统综合征冠状病毒2型感染的情况下,辅以抗病毒药物瑞德西韦,以及最近的莫努匹拉韦、尼马特雷韦/利托那韦和Janus激酶(JAK)抑制剂托法替尼和巴里西替尼。脓毒症和严重的SARS-CoV-2感染/新冠肺炎在病理生理学和促炎介质水平上有许多共同特征,因此能够制定共同的疾病管理策略。成功靶向脓毒症和严重SARS-CoV-2感染/新冠肺炎的预后严重性和死亡率标志物五唑菌素3(PTX3)的新想法;补体(C3/C3a/C3aR和C5/C5a/C5aR轴);肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β和IL-6的表达;IL-6触发血管内皮细胞中C5aR受体的表达;以及抗炎IL-10的释放仍然缺失。具有溶酶运动特征的小分子,如已批准的药物阿米替林、地氯雷他定、氟伏沙明、氮卓斯汀和氨溴索,已在败血症啮齿类动物模型或新冠肺炎临床试验中证明其临床益处;然而,它们的确切作用方式还有待充分阐明。针对疾病相关靶点,如宿主细胞的病毒感染、toll样受体(TLRs)的脱落、促炎介质如TNF-α、IL-1β、IL-6、PTX3和补体受体C5aR的表达,突出了这种多靶点方法与当前标准相比的优势。合理调整已批准药物的用途或筛选几乎完全具有溶酶运动药理作用的活性化合物是改善败血症和/或SARS-CoV-2感染及其严重形式新冠肺炎的预防和治疗的重要机会。
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Small molecules targeting endolysosomal acidification and signaling in sepsis and severe SARS-CoV-2 infection/COVID-19
Sepsis and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and its severe form coronavirus disease 2019 (COVID-19), represent the major medical challenges of the modern era. Therapeutic options are limited, mostly symptomatic, partially relying on antibodies and corticosteroids and, in the case of SARS-CoV-2 infection, supplemented by the antiviral drug remdesivir, and more recently by molnupiravir, nirmatrelvir/ritonavir, and the Janus kinase (JAK) inhibitors tofacitinib and baricitinib. Sepsis and severe SARS-CoV-2 infection/COVID-19 share many features at the level of pathophysiology and pro-inflammatory mediators, thus enabling a common disease management strategy. New ideas in successfully targeting the prognostic severity and mortality marker pentraxin 3 (PTX3) in sepsis and severe SARS-CoV-2 infection/COVID-19; the complement (C3/C3a/C3aR and C5/C5a/C5aR axis); tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 expression; IL-6-triggered expression of C5aR receptor in vascular endothelial cells; and release of anti-inflammatory IL-10 are still missing. Small molecules with lysosomotropic characteristics such as the approved drugs amitriptyline, desloratadine, fluvoxamine, azelastine, and ambroxol have demonstrated their clinical benefits in rodent models of sepsis or clinical trials in COVID-19; however, their exact mode of action remains to be fully elucidated. Addressing disease-relevant targets such as viral infection of host cells, shedding of toll-like receptors (TLRs), expression of pro-inflammatory mediators such as TNF-α, IL-1β, IL-6, PTX3, and the complement receptor C5aR, highlight the advantages of this multi-target approach in comparison to current standards. Rational drug repurposing of approved drugs or screening for active compounds with virtually exclusively lysosomotropic pharmacologic effects is a major opportunity to improve prophylaxis and treatment of sepsis and/or SARS-CoV-2 infection, and its severe form COVID-19.
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