Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID-19.
Human recombinant soluble ACE2 (hrsACE2) shows promise for treating severe COVID-19.
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DOI：
10.1038/s41392-020-00374-6
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发表时间：
2020-11-03
影响因子：
39.3
通讯作者：
Stockand JD
中科院分区：
文献类型：
--
作者：
Abd El-Aziz TM;Al-Sabi A;Stockand JD
Zoufaly等人最近发表在《柳叶刀呼吸医学》上的一项研究描述了第一位用人重组可溶性血管紧张素转换酶-2（hrsACE 2）成功治疗的严重COVID-19患者的令人鼓舞的数据。1已发表的数据记录了适应性免疫反应的治疗，病毒从血清，鼻腔和肺部迅速消失，以及对COVID-19病理学至关重要的炎性细胞因子水平降低。值得注意的是，hrsACE 2的使用并不妨碍中和抗体的产生，导致治疗患者的临床显著改善。严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）的大流行传播导致100多万人死于COVID-19。因此，对病毒病理生理学的重要见解可能有助于寻找有效的疫苗和治疗方案。除了寻找病毒复制抑制剂外，另一种策略是阻断病毒的细胞靶点血管紧张素转换酶-2（ACE 2）。2 ACE 2是SARS-CoV-2的关键受体靶点，在COVID-19的发病机制中起着至关重要的作用，因为它使病毒能够进入靶细胞（图1）。ACE 2与SARS-CoV-2刺突糖蛋白的受体结合结构域（RBD）之间的结合亲和力比与SARS-CoV的RBD之间的结合亲和力高10至20倍，这可能支持了SARS-CoV-2感染的更高致病性。ACE 2是一种跨膜蛋白，通常以其羧肽酶活性及其在肾素-血管紧张素系统中的生理作用而闻名。ACE 2将血管紧张素II水解为其代谢产物血管紧张素1-7，将血管紧张素I水解为其代谢产物血管紧张素1-9，以保护不同组织免受损伤（图1）。3 ACE 2在几种人体器官中以不同水平表达。它在肺部高度表达（在II型肺泡上皮细胞表面），心脏（对心肌细胞、冠状血管内皮细胞和血管平滑肌）、肾（在近端小管细胞上）和小肠虽然膜结合的ACE 2可以介导SARS-CoV-2进入细胞，SARS-CoV-2是ACE 2的一种遗传修饰的可溶形式，称为hrsACE 2，可能减少SARS-CoV-2竞争膜结合ACE 2的细胞进入。APN 001是由Apeiron Biologics设计的hrsACE 2，用于模拟人类酶ACE 2。因此，它可以减少SARS-CoV-2的细胞进入，以最大限度地减少肺损伤和多器官功能障碍（图1）。这一理论观点的实验支持来自体外研究，表明hrsACE 2在细胞培养、工程化人血管和肾类器官中将SARS-CoV-2的病毒生长降低了1000-5000倍。4迄今为止，hrsACE 2已被证明在I期研究中的89名健康志愿者和急性胰腺炎患者中是安全和耐受的。
A recent study by Zoufaly et al. published in The Lancet Respiratory Medicine describes encouraging data from the first severe COVID-19 patient successfully treated with human recombinant soluble angiotensin-converting enzyme-2 (hrsACE2). 1 The published data document upon treatment of an adaptive immune response, the disappearance of the virus swiftly from the serum, the nasal cavity and lungs, and a reduction of inflammatory cytokine levels that are critical for COVID-19 pathology. Notably, the use of hrsACE2 did not impede the generation of neutralizing antibodies, leading to a significant clinical improvement of the treated patient. A pandemic spread of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for more than one million deaths due to COVID-19. Therefore, important insights into the viral pathophysiology may facilitate the search for an effective vaccine and treatment option. In addition to finding viral replication inhibitors, another strategy is to block the cellular target of the virus, angiotensin-converting enzyme-2 (ACE2). 2 ACE2 is a crucial receptor target of SARS-CoV-2, which plays a vital role in the pathogenesis of COVID-19, as it enables viral entry into target cells (Fig. 1). The binding affinity between ACE2 and the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein is 10-to 20-fold higher compared to that with the RBD of SARS-CoV, which likely underpins the higher pathogenesis of SARS-CoV-2 infections. ACE2 is a transmembrane protein typically known for its carboxypeptidase activity and its physiological role in the renin-angiotensin system. ACE2 hydrolyzes angiotensin II to its metabolite, angiotensin 1-7 and angiotensin I to angiotensin 1-9 to protect diverse tissues from injury (Fig. 1). 3 ACE2 is expressed in several human organs at varying levels. It is highly expressed in the lungs (on the surface of type II alveolar epithelial cells), heart (on myocardial cells, coronary vascular endothelial cells, and vascular smooth muscle), kidney (on proximal tubule cells), and small intestine (on the enterocytes).While membrane-bound ACE2 may mediate cell entry of SARS-CoV-2, a genetically modified soluble form of ACE2, called hrsACE2, may decrease cell entry of SARS-CoV-2 competing for membranebound ACE2. APN001 is a hrsACE2 designed by Apeiron Biologics to imitate the human enzyme ACE2. As such, it may decrease cell entry of SARS-CoV-2 to minimize lung injury, and multiple organ dysfunction (Fig. 1). Experimental support for this theoretical idea has come from in vitro studies showing that hrsACE2 reduces viral growth of SARS-CoV-2 by a factor of 1000-5000 in cell-culture, engineered human blood vessels and kidney organoids. 4 To date, hrsACE2 has been documented to be safe and tolerable in 89 healthy volunteers in phase-I studies and patients with acute
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影响因子：
82.9
作者：
Kuba K;Imai Y;Rao S;Gao H;Guo F;Guan B;Huan Y;Yang P;Zhang Y;Deng W;Bao L;Zhang B;Liu G;Wang Z;Chappell M;Liu Y;Zheng D;Leibbrandt A;Wada T;Slutsky AS;Liu D;Qin C;Jiang C;Penninger JM
通讯作者：
Penninger JM
影响因子：
64.5
作者：
Walls, Alexandra C.;Park, Young-Jun;Veesler, David
通讯作者：
Veesler, David
DOI：
10.1016/s2213-2600(20)30418-5
发表时间：
2020-11
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Zoufaly A;Poglitsch M;Aberle JH;Hoepler W;Seitz T;Traugott M;Grieb A;Pawelka E;Laferl H;Wenisch C;Neuhold S;Haider D;Stiasny K;Bergthaler A;Puchhammer-Stoeckl E;Mirazimi A;Montserrat N;Zhang H;Slutsky AS;Penninger JM
通讯作者：
Penninger JM
影响因子：
4.5
作者：
Haschke, Manuel;Schuster, Manfred;Kraehenbuehl, Stephan
通讯作者：
Kraehenbuehl, Stephan
影响因子：
64.5
作者：
Monteil, Vanessa;Kwon, Hyesoo;Penninger, Josef M.
通讯作者：
Penninger, Josef M.