한빛사논문
Simranjeet Singh Sekhon1 Woo-Ri Shin1 Sang Yong Kim2 Dong-Seok Jeong3 Wooil Choi4 Bong-Keun Choi5 Jiho Min4 Ji-Young Ahn1 Yang-Hoon Kim1
1Department of Microbiology, ChungbukNational University, Seowon-Gu, Cheongju,South Korea
2Department of Food Science andBiotechnology, Shin Ansan University,Danwon-Gu, Ansan, Republic of Korea
3SEJONGBIO, Heungdeok-gu, Cheongju-si,Chungcheongbuk-do, Republic of Korea
4Graduate School of Semiconductor andChemical Engineering, Jeonbuk NationalUniversity, Jeonju, Korea
5NUON Co., Ltd, Jungwon-gu, Seongnam,Gyunggi, Korea
Simranjeet Singh Sekhon, Woo-Ri Shin, and Sang Yong Kim contributed equally to this work.
Correspondence: Jiho Min, Ji-Young Ahn and Yang-Hoon Kim
Abstract
Human cyclophilin A (hCypA) is important for the replication of multiple coronaviruses (CoVs), and cyclosporine A inhibitors can suppress CoVs. The emergence of rapidly spreading severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has sparked concerns that mutations affect the binding ability of the spike (S) protein to the angiotensin-converting enzyme 2 (ACE2) cell receptor, affecting the severity of coronavirus disease (COVID-19). Far-western blotting and surface plasmon resonance (SPR) results revealed that hCypA interacts strongly with the viral SARS-CoV-2 receptor-binding domain (RBD), with a binding affinity of 6.85 × 10−8 M. The molecular interaction between hCypA and the viral protein interface was shown using three-dimensional structural analysis, which revealed the blocking of key residues on the RBD interface by hCypA. The RBD facilitates binding to the ACE2 receptor. The hCypA–S protein complex suppressed the binding of RBD to the ACE2 receptor, which a required event for CoV entry into the host cell. The reliability of this postulated blocking mechanism of the hCypA–SARS-CoV2 RBD complex with ACE was confirmed by SPR and molecular interaction lateral flow (MILF) strip assay, which offers the immunochromatographic signal read-outs. The emergence of new SARS-CoV-2 variants with key mutations in RBD had a negligible effect on the binding of the RBD variants to hCypA, indicating an effective mitigation strategy for SARS-CoV-2 variants. The MILF strip assay results also highlight the neutralizing effect of hCypA by effectively blocking RBD (wild type and its variants) from binding ACE2. Given the importance of hCypA in viral entry regulation, it has the potential to be used as a target for antiviral therapy.
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