Transmembrane protease serine 2 (TMPRSS2) inhibitors screened from an Fv-antibody library for preventing SARS-CoV-2 infection

IF 3.597 Q2 Pharmacology, Toxicology and Pharmaceutics
MedChemComm Pub Date : 2025-02-13 DOI:10.1039/D4MD00992D
Jaeyong Jung, Jeong Soo Sung, Soonil Kwon, Hyung Eun Bae, Min-Jung Kang, Joachim Jose, Misu Lee and Jae-Chul Pyun
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引用次数: 0

Abstract

Fv-antibodies targeting the transmembrane protease serine 2 (TMPRSS2) were screened from an Fv-antibody library for inhibiting SARS-CoV-2 infection. Fv-antibodies were derived from the variable region of heavy-chain immunoglobulin G (IgG), which consisted of three complementarity-determining regions (CDRs) and frame regions (FRs). The Fv-antibody library was prepared through site-directed mutagenesis of CDR3 region. The proteolytic cleavage site (S2′ site) of TMPRSS2 on the spike protein (SP) of SARS-CoV-2 was used as a screening probe for the library. Two Fv-antibodies were screened and subsequently expressed as soluble recombinant proteins. The binding affinities of the expressed Fv-antibodies were estimated using a surface plasmon resonance (SPR) biosensor. The two expressed Fv-antibodies specifically bound to the active site of TMPRSS2 which interacts with S2′ site in the proprotein convertase (PPC) region. The neutralizing activities of the two expressed Fv-antibodies were demonstrated using a cell-based infection assay with pseudo-viruses that expressed the SP of four types of SARS-CoV-2 variants: Wu-1 (D614), Delta (B.1.617.2), Omicron (BA.2), and Omicron (BA.4/5). Additionally, a docking simulation was performed to analyze the interaction between the screened Fv-antibodies and the active sites of TMPRSS2.

从fv抗体文库中筛选跨膜蛋白酶丝氨酸2 (TMPRSS2)抑制剂预防SARS-CoV-2感染
从fv抗体文库中筛选到靶向跨膜蛋白酶丝氨酸2 (TMPRSS2)的fv抗体,用于抑制SARS-CoV-2感染。fv抗体来源于重链免疫球蛋白G (IgG)的可变区,由3个互补决定区(cdr)和框架区(FRs)组成。通过CDR3区定点诱变制备fv抗体文库。以TMPRSS2在SARS-CoV-2刺突蛋白(SP)上的蛋白水解裂解位点(S2′位点)作为文库的筛选探针。筛选了两种fv抗体,随后将其表达为可溶性重组蛋白。用表面等离子体共振(SPR)生物传感器估计表达的fv抗体的结合亲和力。这两种表达的fv抗体特异性结合TMPRSS2的活性位点,该活性位点与蛋白转化酶(PPC)区域的S2位点相互作用。用表达四种SARS-CoV-2变体SP的假病毒(Wu-1 (D614)、Delta (B.1.617.2)、Omicron (BA.2)和Omicron (BA.4/5))的细胞感染试验证明了两种表达的fv抗体的中和活性。此外,对接模拟分析了筛选到的fv抗体与TMPRSS2活性位点的相互作用。
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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来源期刊
MedChemComm
MedChemComm BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
4.70
自引率
0.00%
发文量
0
审稿时长
2.2 months
期刊介绍: Research and review articles in medicinal chemistry and related drug discovery science; the official journal of the European Federation for Medicinal Chemistry. In 2020, MedChemComm will change its name to RSC Medicinal Chemistry. Issue 12, 2019 will be the last issue as MedChemComm.
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