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Screening and Characterization of Shark-Derived VNARs against SARS-CoV-2 Spike RBD Protein.
Chen, Yu-Lei; Lin, Jin-Jin; Ma, Huan; Zhong, Ning; Xie, Xin-Xin; Yang, Yunru; Zheng, Peiyi; Zhang, Ling-Jing; Jin, Tengchuan; Cao, Min-Jie.
  • Chen YL; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
  • Lin JJ; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
  • Ma H; CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science & Technology of China, Hefei 230007, China.
  • Zhong N; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
  • Xie XX; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
  • Yang Y; CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science & Technology of China, Hefei 230007, China.
  • Zheng P; CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science & Technology of China, Hefei 230007, China.
  • Zhang LJ; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
  • Jin T; CAS Key Laboratory of Innate Immunity and Chronic Disease, Division of Life Sciences and Medicine, University of Science & Technology of China, Hefei 230007, China.
  • Cao MJ; College of Ocean Food and Biological Engineering, Jimei University, Xiamen 361021, China.
Int J Mol Sci ; 23(18)2022 Sep 18.
Article in English | MEDLINE | ID: covidwho-2039875
ABSTRACT
The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein is the major target for antibody therapeutics. Shark-derived variable domains of new antigen receptors (VNARs) are the smallest antibody fragments with flexible paratopes that can recognize protein motifs inaccessible to classical antibodies. This study reported four VNARs binders (JM-2, JM-5, JM-17, and JM-18) isolated from Chiloscyllium plagiosum immunized with SARS-CoV-2 RBD. Biolayer interferometry showed that the VNARs bound to the RBD with an affinity KD ranging from 38.5 to 2720 nM, and their Fc fusions had over ten times improved affinity. Gel filtration chromatography revealed that JM-2-Fc, JM-5-Fc, and JM-18-Fc could form stable complexes with RBD in solution. In addition, five bi-paratopic VNARs, named JM-2-5, JM-2-17, JM-2-18, JM-5-18, and JM-17-18, were constructed by fusing two VNARs targeting distinct RBD epitopes based on epitope grouping results. All these bi-paratopic VNARs except for JM-5-18 showed higher RBD binding affinities than its component VNARs, and their Fc fusions exhibited further enhanced binding affinities, with JM-2-5-Fc, JM-2-17-Fc, JM-2-18-Fc, and JM-5-18-Fc having KD values lower than 1 pM. Among these Fc fusions of bi-paratopic VNARs, JM-2-5-Fc, JM-2-17-Fc, and JM-2-18-Fc could block the angiotensin-converting enzyme 2 (ACE2) binding to the RBD of SARS-CoV-2 wildtype, Delta, Omicron, and SARS-CoV, with inhibition rates of 48.9~84.3%. Therefore, these high-affinity VNAR binders showed promise as detectors and therapeutics of COVID-19.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sharks / COVID-19 Drug Treatment Topics: Variants Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms231810904

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Sharks / COVID-19 Drug Treatment Topics: Variants Limits: Animals / Humans Language: English Year: 2022 Document Type: Article Affiliation country: Ijms231810904