1. The Development of a Novel Nanobody Therapeutic for SARS-CoV-2
- Author
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Jian Shang, Aleksandra Drelich, Ke Shi, Stanley Perlman, Christopher Massey, Hideki Aihara, Chien Te K. Tseng, Lanying Du, Vivian Tat, Aaron M. LeBeau, Jian Zheng, Joseph P. Gallant, Yushun Wan, Gang Ye, Fang Li, Kempaiah Rayavara Kempaiah, Wanbo Tai, Abby E. Odle, and Molly A. Vickers
- Subjects
Male ,Models, Molecular ,Drug ,Phage display ,drug pharmacokinetics ,Protein Conformation ,media_common.quotation_subject ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,ACE2 ,spike protein receptor-binding domain ,Mice, Transgenic ,Pharmacology ,spike protein ,Antibodies, Viral ,Article ,crystal structures ,Mice ,In vivo ,Animals ,Humans ,Medicine ,Pandemics ,single-chain antibody from camelids ,media_common ,Microbiology and Infectious Disease ,biology ,SARS-CoV-2 ,business.industry ,animal model ,COVID-19 ,Single-Domain Antibodies ,Antibodies, Neutralizing ,In vitro ,Virus ,COVID-19 Drug Treatment ,Bioavailability ,Mice, Inbred C57BL ,HEK293 Cells ,Viral Receptor ,virus neutralization ,Spike Glycoprotein, Coronavirus ,biology.protein ,Receptors, Virus ,Angiotensin-Converting Enzyme 2 ,receptor-binding domain ,Antibody ,business ,Research Article ,Protein Binding - Abstract
Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a novel series of single-domain antibodies (i.e., nanobody), Nanosota-1, from a camelid nanobody phage display library. Structural data showed thatNanosota-1bound to the oft-hidden receptor-binding domain (RBD) of SARS-CoV-2 spike protein, blocking out viral receptor ACE2. The lead drug possessing an Fc tag (Nanosota-1C-Fc) bound to SARS-CoV-2 RBD with a Kdof 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND50of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose,Nanosota-1C-Fcdemonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs,Nanosota-1C-Fcwas produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis ofNanosota-1C-Fc documented a greater than 10-dayin vivohalf-life efficacy and high tissue bioavailability.Nanosota-1C-Fcis a potentially effective and realistic solution to the COVID-19 pandemic.Impact statementPotent and low-costNanosota-1drugs block SARS-CoV-2 infections bothin vitroandin vivoand act both preventively and therapeutically.
- Published
- 2020
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