Near-atomic look at three ways to thwart SARS-CoV-2 variants

Three types of nanobodies are able to impede the release of a spike protein from SARS-CoV-2. Credit: CWRUSARS-CoV-2 nanobodiesmicroscopic molecules developed at the University of Pittsburgh School of Medicine that neutralize the virus in animalsare remarkably active against mutations found in variants, including Delta, according to new research by Pitt and Case Western Reserve University scientists.Today's Nature Communications announcement reveals three mechanisms through which nanobodies can disarm the virus. They prevent it from infecting cells, and cause 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 coronavirusesincluding variants not yet in circulation.Yi Shi, senior author and assistant professor of cell biology at Pitt, said that this is the first time that anyone has systematically classified ultrapotent Nanobodies based upon their structure. "We have not only revealed the mechanisms that our nanobodies use in defeating SARS-CoV-2 but also provided directions for future therapeutics."Shi and his team revealed that they had isolated tiny but very powerful SARS-CoV-2 antibodies from llamas. These could be used to make inhalable therapeutics for COVID-19. Preclinical research has shown that these nanobodies are capable of treating severe COVID-19 in hamsters. They also reduce virus particles in their lungs by one million times compared to placebo.Shi collaborated with Pitt structural biologists Cheng Zhang and James Conway to study the interaction of nanobodies with the SARS-2 virus. This was done to discover how variants can affect nanobody interactions.The first systematic classification and classification of ultrapotent nanobodies has revealed that microscopic molecules are effective against SARS-CoV-2 in 3 ways. Credit: CWRU"Cryoelectron microscopic has been shown many times to be extremely useful in seeing high-resolution structural data," stated co-senior author Wei Huang (Ph.D.), research scientist at the Case Western Reserve School of Medicine. "Nanobodies are stable and versatile biologics that can also be used in research such as cancer research."Eight powerful nanobodies were selected by the team for further investigation. They first confirmed that many of the nanobodies worked against Alpha, which is associated with the U.K., and Delta, which is associated with India.The nanobodies were also divided into three groups based upon their interaction with spike proteins. These are protrusions that surround the spherical Coronavirus and act like "keys" to allow the virus to enter human cells.The spike protein that binds to Class I in the human cell is not affected by the virus, so it can't be transmitted to the cells.Class II binds to a region on the spike protein that has persisted through several permutations of coronavirusesincluding the original SARS-CoV-1. It may also neutralize SARS CoV-2 and its variants.Class III binds to a particular region of spike protein that larger antibodies can't access. The nanobody binds to this region and prevents the protein folding in the right way to enter human cells.Shi stated that "Describing all the vulnerabilities and ways to defeat SARS-CoV-2 is a huge opportunity." It will help our team to select and refine nanobodies that treat and prevent COVID-19. But it may also lead to a universal vaccine to prevent SARS and other coronavirus-related diseases.Further information: Dapeng Sun et al., Potent neutralizing Nanobodies Resist convergent circulating Variants of SARS-CoV-2 through Targeting Diverse and Conserved Epitopes. Nature Communications (2021). Information from Nature Communications Dapeng Sun et al., Potent neutralizing Nanobodies Resist convergent circulating Varianten of SARS-CoV-2 through targeting diverse and preserved epitopes. Journal information: Nature Communications (2021). DOI: 10.1038/s41467-021-24963-3