A novel nanobody broadly neutralizes SARS‐CoV‐2 via induction of spike trimer dimers conformation
Yang Yang,
Junfang Zhang,
Shengnan Zhang,
Chenhui Zhang,
Chenguang Shen,
Shuo Song,
Yanqun Wang,
Yun Peng,
Xiaohua Gong,
Jun Dai,
Chongwei Xie,
Tatyana Aleksandrovna Khrustaleva,
Vladislav Victorovich Khrustalev,
Yongting Huo,
Di Lu,
Da Yao,
Jincun Zhao,
Yingxia Liu,
Hongzhou Lu
Affiliations
Yang Yang
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Junfang Zhang
Medical Research CenterYuebei People's Hospital, Shantou University Medical CollegeShaoguan China
Shengnan Zhang
State Key Laboratory of Respiratory Disease National Clinical Researcher Center for Respiratory Diseases Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
Chenhui Zhang
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Chenguang Shen
BSL‐3 Laboratory (Guangdong) Guangdong Provincial Key Laboratory of Tropical Disease Research School of Public Health Department of Laboratory Medicine Zhujiang Hospital Southern Medical University Guangzhou China
Shuo Song
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Yanqun Wang
State Key Laboratory of Respiratory Disease National Clinical Researcher Center for Respiratory Diseases Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
Yun Peng
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Xiaohua Gong
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Jun Dai
Health and Quarantine Laboratory Guangzhou Customs District Technology Centre Guangzhou Guangdong China
Chongwei Xie
Medical Research CenterYuebei People's Hospital, Shantou University Medical CollegeShaoguan China
Tatyana Aleksandrovna Khrustaleva
Multidisciplinary Diagnostic Laboratory Institute of Physiology of the National Academy of Sciences of Belarus Minsk Belarus
Vladislav Victorovich Khrustalev
Multidisciplinary Diagnostic Laboratory Institute of Physiology of the National Academy of Sciences of Belarus Minsk Belarus
Yongting Huo
Guangdong Fapon Biopharma Inc. Shenzhen China
Di Lu
Guangdong Fapon Biopharma Inc. Shenzhen China
Da Yao
Department of Thoracic Surgery The First Affiliated Hospital of Shenzhen University Shenzhen Second People's Hospital Shenzhen Guangdong China
Jincun Zhao
State Key Laboratory of Respiratory Disease National Clinical Researcher Center for Respiratory Diseases Guangzhou Institute of Respiratory Health The First Affiliated Hospital of Guangzhou Medical University Guangzhou Guangdong China
Yingxia Liu
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Hongzhou Lu
Shenzhen Key Laboratory of Pathogen and Immunity Shenzhen Clinical Research Center for infectious disease Shenzhen Third People's Hospital Second Hospital Affiliated to Southern University of Science and Technology Shenzhen China
Abstract The ongoing mutations of the SARS‐CoV‐2 pose serious challenges to the efficacy of the available antiviral drugs, and new drugs with fantastic efficacy are always deserved investigation. Here, a nanobody called IBT‐CoV144 is reported, which exhibits broad neutralizing activity against SARS‐CoV‐2 by inducing the conformation of spike trimer dimers. IBT‐CoV144 was isolated from an immunized alpaca using the RBD of wild‐type SARS‐CoV‐2, and it showed strong cross‐reactive binding and neutralizing potency against diverse SARS‐CoV‐2 variants, including Omicron subvariants. Moreover, the prophylactically and therapeutically intranasal administration of IBT‐CoV144 confers fantastic protective efficacy against the challenge of Omicron BA.1 variant in BALB/c mice model. The structure analysis of the complex between spike (S) protein, conducted using Cryo‐EM, revealed a special conformation known as the trimer dimers. This conformation is formed by two trimers, with six RBDs in the “up” state and bound by six VHHs. IBT‐CoV144 binds to the lateral region of the RBD on the S protein, facilitating the aggregation of S proteins. This aggregation results in steric hindrance, which disrupts the recognition of the virus by ACE2 on host cells. The discovery of IBT‐CoV144 will provide valuable insights for the development of advanced therapeutics and the design of next‐generation vaccines.
