After one year of COVID-19 Pandemic and Hundreds of Suggested Drugs, Will Cathepsin L Inhibitors be the Solution?

IF 4.1 Q1 HEALTH POLICY & SERVICES
A. Ahmed
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Abstract

Cysteine cathepsins are defined as lysosomal enzymes which are member of the papain family. Cysteine cathepsins (Cts) prevalently exist in whole organisms varying from prokaryotes to mammals and possess in their active site greatly conserved residue of cysteine. Cts are engaged in the digestion of cellular protein, activation of zymogen, and remodeling of extracellular matrix (ECM). Host cells are entered by SARS-CoV-2 via endocytosis. Cathepsin L and phosphatidylinositol 3-phosphate 5-kinase are crucial in terms of the endocytosis by cleaving the spike protein, which permits viral membrane fusion with endosomal membrane, and succeeded by the releasing of viral genome to the host cell. Thereby, inhibition of cathepsin L may be advantageous in terms of decreasing infection caused by SARS-CoV-2. Coordinate inhibition of multiple Cts and lysosomal function by different drugs and biological agents might be of value for some purposes such as parasite or viral infections and anti-neoplastic applications. It has been found that Zn 2+ deficiency or dysregulation leads to an exaggerated activity of Cysteine cathepsin increasing the autoimmune/inflammatory response. At this purpose Zn 2+ metal can be safely combined with a drug that increases the anti-proteolytic effect of endogenous Zn 2+ lowering the excessive activity of some CysCts. Biguanide derivatives complex with Zn 2+ have been found to be promising inhibitors of CysCts protease reactions. Molecular docking studies of Cathepsin L Inhibited by Metformin-Zn+2 complex have been performed showing two strong key interactions ( Cys-25&His-163) and an extra H-bond with Asp-163 compared to the co-crystallized Zn +2 (PDB ID 4axl).
经过一年的COVID-19大流行和数百种推荐药物,组织蛋白酶L抑制剂会是解决方案吗?
半胱氨酸组织蛋白酶被定义为属于木瓜蛋白酶家族的溶酶体酶。半胱氨酸组织蛋白酶(Cts)普遍存在于从原核生物到哺乳动物的整个生物体中,其活性位点具有非常保守的半胱氨酸残基。Cts参与细胞蛋白质的消化、酶原的激活和细胞外基质(ECM)的重塑。宿主细胞通过内吞作用进入严重急性呼吸系统综合征冠状病毒2型。组织蛋白酶L和磷脂酰肌醇3-磷酸5-激酶通过裂解刺突蛋白进行内吞作用至关重要,刺突蛋白允许病毒膜与内涵体膜融合,并成功地将病毒基因组释放到宿主细胞。因此,抑制组织蛋白酶L在减少由严重急性呼吸系统综合征冠状病毒2引起的感染方面可能是有利的。不同药物和生物制剂对多种Ct和溶酶体功能的协同抑制可能对某些目的有价值,如寄生虫或病毒感染和抗肿瘤应用。已经发现Zn2+缺乏或失调导致半胱氨酸组织蛋白酶的活性增强,从而增加自身免疫/炎症反应。为此,Zn2+金属可以与一种药物安全地结合,该药物增加内源性Zn2+的抗蛋白水解作用,降低一些CysCts的过度活性。双胍衍生物与Zn2+的配合物已被发现是CysCts蛋白酶反应的有前途的抑制剂。Metformin-Zn+2复合物抑制组织蛋白酶L的分子对接研究表明,与共结晶的Zn+2(PDB ID 4axl)相比,组织蛋白酶有两个强的关键相互作用(Cys-25和His-163)和与Asp-163的额外氢键。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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