Abstract：
The enzymatic activities of Furin, Transmembrane serine proteinase 2 (TMPRSS2), Cathepsin L (CTSL), and Angiotensin-converting enzyme 2 (ACE2) receptor binding are necessary for the entry of coronaviruses into host cells. Precise inhibition of these key proteases in ACE2+ lung cells during a viral infection cycle shall prevent viral Spike (S) protein activation and its fusion with a host cell membrane, consequently averting virus entry to the cells. In this study, dual-drug-combined (TMPRSS2 inhibitor Camostat and CTSL inhibitor E-64d) nanocarriers (NCs) are constructed conjugated with an anti-human ACE2 (hACE2) antibody and employ Red Blood Cell (RBC)-hitchhiking, termed \"Nanoengineered RBCs,\" for targeting lung cells. The significant therapeutic efficacy of the dual-drug-loaded nanoengineered RBCs in pseudovirus-infected K18-hACE2 transgenic mice is reported. Notably, the modular nanoengineered RBCs (anti-receptor antibody+NCs+RBCs) precisely target key proteases of host cells in the lungs to block the entry of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), regardless of virus variations. These findings are anticipated to benefit the development of a series of novel and safe host-cell-protecting antiviral therapies.
摘要：
弗林蛋白酶的酶活性，跨膜丝氨酸蛋白酶2（TMPRSS2），组织蛋白酶L(CTSL),和血管紧张素转换酶2（ACE2）受体结合是冠状病毒进入宿主细胞所必需的。在病毒感染周期中精确抑制ACE2+肺细胞中的这些关键蛋白酶应防止病毒S蛋白活化及其与宿主细胞膜的融合。从而避免病毒进入细胞。在这项研究中,我们构建了与抗hACE2抗体缀合的双药联合（TMPRSS2抑制剂Camostat和CTSL抑制剂E-64d）纳米载体（NCs），并采用RBC搭便车，称为“纳米工程红细胞，“用于靶向肺细胞。我们报告了双药纳米工程红细胞在假病毒感染的K18-hACE2转基因小鼠中的显着治疗效果。值得注意的是,我们的模块化纳米工程RBC(抗受体抗体+NCs+RBC)精确靶向肺部宿主细胞的关键蛋白酶,以阻断SARS-CoV-2的进入,而不管病毒的变异.我们的发现预计将有利于一系列新型和安全的宿主细胞保护抗病毒疗法的发展。本文受版权保护。保留所有权利。
