SARS-CoV-2 nanobodies—microscopic molecules developed at the University of Pittsburgh School of Medicine that neutralize the virus in animals—are remarkably active against mutations found in variants, including Delta, according to new research by Pitt and Case Western Reserve University scientists.
The findings, announced in Nature Communications, describe three mechanisms by which the nanobodies disarm the virus, blocking it from infecting cells and causing COVID-19. The near-atomic-level structural analysis provides guidance for the development of future vaccines and therapeutics that may work against a wide variety of coronaviruses—including variants not yet in circulation.
“This is the first time anyone has systematically classified ultrapotent nanobodies based on their structure,” said senior author Yi Shi, assistant professor of cell biology at Pitt. “By doing this, we’ve not only provided details on the mechanisms our nanobodies use to defeat SARS-CoV-2 but also revealed directions for how to design future therapeutics.”
Late last year, Shi and his team announced that they’d extracted tiny, but extremely powerful, SARS-CoV-2 antibody fragments from llamas, which could be fashioned into inhalable therapeutics to prevent and treat COVID-19. Since then, preclinical studies have verified that the potent nanobodies prevent and treat severe COVID-19 in hamsters, reducing virus particles in their respiratory tracts by a million-fold compared to placebo.
In this latest study, Shi partnered with Pitt structural biologists Cheng Zhang and James Conway as well as pharmacologists, structural biologists and biochemists at Case Western Reserve, to use high-resolution cryoelectron microscopy to observe exactly how the nanobodies interact with the SARS-CoV-2 virus to stop it from infecting cells and discover how mutations found in variants may affect nanobody interactions.
“Cryoelectron microscopy has been demonstrated many times to be an extremely useful tool to see high-resolution structural information,” said co-senior author Wei Huang, research scientist in the Department of Pharmacology at the Case Western Reserve School of Medicine. “And nanobodies are versatile and stable biologics that can be used in other research, such as cancer.”