TY - JOUR TI - The development of Nanosota-1 as anti-SARS-CoV-2 nanobody drug candidates AU - Ye, Gang AU - Gallant, Joseph AU - Zheng, Jian AU - Massey, Christopher AU - Shi, Ke AU - Tai, Wanbo AU - Odle, Abby AU - Vickers, Molly AU - Shang, Jian AU - Wan, Yushun AU - Du, Lanying AU - Aihara, Hideki AU - Perlman, Stanley AU - LeBeau, Aaron AU - Li, Fang A2 - Schoggins, John W A2 - Van der Meer, Jos W A2 - Wu, Zhiwei VL - 10 PY - 2021 DA - 2021/08/02 SP - e64815 C1 - eLife 2021;10:e64815 DO - 10.7554/eLife.64815 UR - https://doi.org/10.7554/eLife.64815 AB - 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. KW - COVID-19 KW - single-chain antibody from camelids KW - spike protein receptor-binding domain KW - ACE2 KW - crystal structures KW - virus neutralization KW - animal model KW - drug pharmacokinetics JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -