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

IF 4.1 4区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY RSC medicinal chemistry 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, Jae-Chul Pyun
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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.

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