The development of <i>Nanosota</i>-<i>1</i> as anti-SARS-CoV-2 nanobody drug candidates.

Abstract

Combating the COVID-19 pandemic requires potent and low-cost therapeutics. We identified a series of single-domain antibodies (i.e., nanobody), <i>Nanosota-1</i>, from a camelid nanobody phage display library. Structural data showed that <i>Nanosota-1</i> 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 (<i>Nanosota-1C-Fc</i>) 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, <i>Nanosota-1C-Fc</i> demonstrated preventive and therapeutic efficacy against live SARS-CoV-2 infection in both hamster and mouse models. Unlike conventional antibodies, <i>Nanosota-1C-Fc</i> was produced at high yields in bacteria and had exceptional thermostability. Pharmacokinetic analysis of <i>Nanosota-1C-F</i>c documented an excellent in vivo stability and a high tissue bioavailability. As effective and inexpensive drug candidates, <i>Nanosota-1</i> may contribute to the battle against COVID-19.