TY - JOUR
T1 - A novel nanobody targeting middle east respiratory syndrome coronavirus (MERS-CoV) receptor-binding domain has potent cross-neutralizing activity and protective efficacy against MERS-CoV
AU - Zhao, Guangyu
AU - He, Lei
AU - Sun, Shihui
AU - Qiu, Hongjie
AU - Tai, Wanbo
AU - Chen, Jiawei
AU - Li, Jiangfan
AU - Chen, Yuehong
AU - Guo, Yan
AU - Wang, Yufei
AU - Shang, Jian
AU - Ji, Kaiyuan
AU - Fan, Ruiwen
AU - Du, Enqi
AU - Jiang, Shibo
AU - Li, Fang
AU - Du, Lanying
AU - Zhou, Yusen
N1 - Publisher Copyright:
© 2018 American Society for Microbiology. All Rights Reserved.
PY - 2018/9/1
Y1 - 2018/9/1
N2 - The newly emerged Middle East respiratory syndrome coronavirus (MERSCoV) continues to infect humans and camels, calling for efficient, cost-effective, and broad-spectrum strategies to control its spread. Nanobodies (Nbs) are single-domain antibodies derived from camelids and sharks and are potentially cost-effective antivirals with small size and great expression yield. In this study, we developed a novel neutralizing Nb (NbMS10) and its human-Fc-fused version (NbMS10-Fc), both of which target the MERS-CoV spike protein receptor-binding domain (RBD). We further tested their receptor-binding affinity, recognizing epitopes, cross-neutralizing activity, half-life, and efficacy against MERS-CoV infection. Both Nbs can be expressed in yeasts with high yield, bind to MERS-CoV RBD with high affinity, and block the binding of MERS-CoV RBD to the MERS-CoV receptor. The binding site of the Nbs on the RBD was mapped to be around residue Asp539, which is part of a conserved conformational epitope at the receptor-binding interface. NbMS10 and NbMS10-Fc maintained strong cross-neutralizing activity against divergent MERS-CoV strains isolated from humans and camels. Particularly, NbMS10-Fc had significantly extended half-life in vivo; a single-dose treatment of NbMS10-Fc exhibited high prophylactic and therapeutic efficacy by completely protecting humanized mice from lethal MERS-CoV challenge. Overall, this study proves the feasibility of producing cost-effective, potent, and broad-spectrum Nbs against MERS-CoV and has produced Nbs with great potentials as anti-MERS-CoV therapeutics.
AB - The newly emerged Middle East respiratory syndrome coronavirus (MERSCoV) continues to infect humans and camels, calling for efficient, cost-effective, and broad-spectrum strategies to control its spread. Nanobodies (Nbs) are single-domain antibodies derived from camelids and sharks and are potentially cost-effective antivirals with small size and great expression yield. In this study, we developed a novel neutralizing Nb (NbMS10) and its human-Fc-fused version (NbMS10-Fc), both of which target the MERS-CoV spike protein receptor-binding domain (RBD). We further tested their receptor-binding affinity, recognizing epitopes, cross-neutralizing activity, half-life, and efficacy against MERS-CoV infection. Both Nbs can be expressed in yeasts with high yield, bind to MERS-CoV RBD with high affinity, and block the binding of MERS-CoV RBD to the MERS-CoV receptor. The binding site of the Nbs on the RBD was mapped to be around residue Asp539, which is part of a conserved conformational epitope at the receptor-binding interface. NbMS10 and NbMS10-Fc maintained strong cross-neutralizing activity against divergent MERS-CoV strains isolated from humans and camels. Particularly, NbMS10-Fc had significantly extended half-life in vivo; a single-dose treatment of NbMS10-Fc exhibited high prophylactic and therapeutic efficacy by completely protecting humanized mice from lethal MERS-CoV challenge. Overall, this study proves the feasibility of producing cost-effective, potent, and broad-spectrum Nbs against MERS-CoV and has produced Nbs with great potentials as anti-MERS-CoV therapeutics.
KW - Cross-neutralization
KW - MERS-CoV
KW - Nanobody
KW - Protective efficacy
KW - Receptor-binding domain
KW - Spike protein
UR - http://www.scopus.com/inward/record.url?scp=85052935582&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052935582&partnerID=8YFLogxK
U2 - 10.1128/JVI.00837-18
DO - 10.1128/JVI.00837-18
M3 - Article
C2 - 29950421
AN - SCOPUS:85052935582
SN - 0022-538X
VL - 92
JO - Journal of virology
JF - Journal of virology
IS - 18
M1 - e00837
ER -