US scientists have found that SARS-CoV-2 nanobodies -- microscopic molecules that neutralise the virus in animals -- are remarkably active against mutations found in variants, including Delta.The study, led by Universities of Pittsburgh and Case Western Reserve, describe three different 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's School of Medicine."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," Shi added.The findings are published in the journal Nature Communications.
For the study, the team used high-resolution cryo electron 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.They confirmed through observations that several of the nanobodies work against Alpha, Delta, and several other SARS-CoV-2 variants of concern.They also classified the nanobodies into three main groups based on how they interact with the spike proteins, which are the protrusions that encircle the spherical coronavirus and act as "keys" that grant the virus entry to human cells.Class I outcompetes the part of the human cell that the spike protein binds to, preventing the virus from gaining entry to cells, while Class II binds to a region on the spike protein that has persisted through several permutations of coronaviruses -- including the original SARS-CoV-1. This means it may neutralize SARS-CoV-2 and its variants, but also other coronaviruses.Class III latches on to a specific region of the spike protein that larger antibodies cannot access. By binding to this area, the nanobody prevents the protein from folding in the way it needs to for entry into human cells."Describing all these vulnerabilities and ways to thwart SARS-CoV-2 and coronaviruses in general has huge potential," said Shi. "It will not only help our team select and refine nanobodies to treat and prevent Covid-19, but it also may lead to a universal vaccine, preventing not just Covid-19, but SARS, MERS and other diseases caused by coronaviruses."