Experimental Cardiology, Department of Internal Medicine, Justus Liebig University, 35392 Giessen, Germany.
DZHK (German Centre for Cardiovascular Research), Department of Cardiology, Kerckhoff Clinic GmbH partner site Rhein-Main, 61231 Bad Nauheim, Germany.
Cells. 2020 Aug 25;9(9):1962. doi: 10.3390/cells9091962.
An outbreak of the novel coronavirus (CoV) SARS-CoV-2, the causative agent of COVID-19 respiratory disease, infected millions of people since the end of 2019, led to high-level morbidity and mortality and caused worldwide social and economic disruption. There are currently no antiviral drugs available with proven efficacy or vaccines for its prevention. An understanding of the underlying cellular mechanisms involved in virus replication is essential for repurposing the existing drugs and/or the discovery of new ones. Endocytosis is the important mechanism of entry of CoVs into host cells. Endosomal maturation followed by the fusion with lysosomes are crucial events in endocytosis. Late endosomes and lysosomes are characterized by their acidic pH, which is generated by a proton transporter V-ATPase and required for virus entry via endocytic pathway. The cytoplasmic cAMP pool produced by soluble adenylyl cyclase (sAC) promotes V-ATPase recruitment to endosomes/lysosomes and thus their acidification. In this review, we discuss targeting the sAC-specific cAMP pool as a potential strategy to impair the endocytic entry of the SARS-CoV-2 into the host cell. Furthermore, we consider the potential impact of sAC inhibition on CoV-induced disease via modulation of autophagy and apoptosis.
自 2019 年底以来，新型冠状病毒（CoV）SARS-CoV-2 引发的 COVID-19 呼吸道疾病已感染数百万人，导致高发病率和死亡率，并造成全球社会和经济混乱。目前尚无已证明有效的抗病毒药物或疫苗可用于预防。了解病毒复制所涉及的基本细胞机制对于重新利用现有药物和/或发现新药物至关重要。内吞作用是 CoV 进入宿主细胞的重要机制。内体成熟后与溶酶体融合是内吞作用的关键事件。晚期内体和溶酶体的特点是酸性 pH 值，这是由质子转运 V-ATPase 产生的，对于通过内吞途径进入病毒是必需的。可溶性腺苷酸环化酶（sAC）产生的细胞质 cAMP 池促进 V-ATPase 募集到内体/溶酶体，从而使它们酸化。在这篇综述中，我们讨论了靶向 sAC 特异性 cAMP 池作为一种潜在策略来削弱 SARS-CoV-2 进入宿主细胞的内吞作用。此外，我们还考虑了通过调节自噬和细胞凋亡，sAC 抑制对 CoV 诱导疾病的潜在影响。
