Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States; Center for Coronavirus Research, University of Minnesota, Saint Paul, United States
Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, United States
Abby Odle
Department of Microbiology and Immunology, University of Iowa, Iowa City, United States
Molly Vickers
Department of Microbiology and Immunology, University of Iowa, Iowa City, United States
Jian Shang
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States; Center for Coronavirus Research, University of Minnesota, Saint Paul, United States
Yushun Wan
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States; Center for Coronavirus Research, University of Minnesota, Saint Paul, United States
Lanying Du
Laboratory of Viral Immunology, Lindsley F. Kimball Research Institute, New York Blood Center, New York, United States
Department of Veterinary and Biomedical Sciences, University of Minnesota, Saint Paul, United States; Center for Coronavirus Research, University of Minnesota, Saint Paul, United States
Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed that Nanosota-1 bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking viral receptor angiotensin-converting enzyme 2 (ACE2). The lead drug candidate possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD ~3000 times more tightly than ACE2 did and inhibited SARS-CoV-2 pseudovirus ~160 times more efficiently than ACE2 did. Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, Nanosota-1 may contribute to the battle against COVID-19.
