Broad neutralizing nanobody against SARS-CoV-2 engineered from pre-designed synthetic library

Liu, Qianyun; Cai, Chenguang; Huang, Yanyan; Zhou, Li; Guan, Yanbin; Fu, Shiying; Lin, Youyou; Yang, Ting; Wan, Nanyan; Zhang, Fengzhi; Sun, Qi; Bai, Ying; Chen, Yu; Liang, Xiaohua; Yan, Huan; Zhang, Zhen; Lan, Ke; Chen, Yu; Li, Xiang; Hou, Shin-Chen; Xiong, Yi

SARS-CoV-2 infection is initiated with Spike glycoprotein binding to the receptor of human angiotensin converting enzyme 2 via its receptor binding domain. Blocking this interaction is considered as an effective approach to inhibit virus infection. Here we report the discovery of a neutralizing nanobody, VHH60, directly produced from a humanized synthetic nanobody library. VHH60 competes with human ACE2 to bind the receptor binding domain of the Spike protein with a KD of 2.56 nM, inhibits infections of both live SARS-CoV-2 and pseudotyped viruses harboring wildtype, escape mutations and prevailing variants at nanomolar level. VHH60 also suppresses SARS-CoV-2 infection and propagation 50-fold better and protects mice from death two times longer than that of control group after live virus inoculation on mice. VHH60 therefore is a powerful synthetic nanobody with a promising profile for disease control against COVID19.