TY - JOUR T1 - The Development of a Novel Nanobody Therapeutic for SARS-CoV-2 JF - bioRxiv DO - 10.1101/2020.11.17.386532 SP - 2020.11.17.386532 AU - Gang Ye AU - Joseph P. Gallant AU - Christopher Massey AU - Ke Shi AU - Wanbo Tai AU - Jian Zheng AU - Abby E. Odle AU - Molly A. Vickers AU - Jian Shang AU - Yushun Wan AU - Aleksandra Drelich AU - Kempaiah R. Kempaiah AU - Vivian Tat AU - Stanley Perlman AU - Lanying Du AU - Chien-Te Tseng AU - Hideki Aihara AU - Aaron M. LeBeau AU - Fang Li Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/11/17/2020.11.17.386532.abstract N2 - 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 that Nanosota-1 bound 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 Kd of 15.7picomolar (∼3000 times more tightly than ACE2 did) and inhibited SARS-CoV-2 infection with an ND50 of 0.16microgram/milliliter (∼6000 times more potently than ACE2 did). Administered at a single dose, Nanosota-1C-Fc demonstrated preventive and therapeutic efficacy in hamsters subjected to SARS-CoV-2 infection. Unlike conventional antibody drugs, Nanosota-1C-Fc was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of Nanosota-1C-Fc documented a greater than 10-day in vivo half-life efficacy and high tissue bioavailability. Nanosota-1C-Fc is a potentially effective and realistic solution to the COVID-19 pandemic.Impact statement Potent and low-cost Nanosota-1 drugs block SARS-CoV-2 infections both in vitro and in vivo and act both preventively and therapeutically. ER -