Researchers at Karolinska University Hospital and the University of Cape Town have identified an antibody fragment that targets the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and potently neutralizes the virus.
Derived from the alpaca, the molecule, called Ty1, is a single domain antibody fragment (nanobody) that targets the spike protein’s receptor-binding domain (RBD) in a way that prevents its interaction with angiotensin-converting enzyme 2 (ACE2) – the host cell receptor that SARS-CoV-2 binds to when infecting cells.
“We provide structural and mechanistic insights that demonstrate that Ty1 prevents RBD binding to its host cell receptor ACE2, and thus prevents SARS-CoV-2 virions from attaching to cells,” write Gerald McInerney (Karolinska University Hospital) and colleagues.
The researchers say their characterization of the nanobody’s binding and neutralizing ability showed it to be the most potent SARS-CoV-2 specific nanobody reported to date.
They also say that, importantly, Ty1 can be readily produced at a very high yield in bacteria, pointing to its excellent potential as a cost-effective and scalable SARS-CoV-2 antiviral agent.
A pre-print version of the paper is available in bioRxiv* while the article undergoes peer review.
Researchers worldwide are working on potential vaccines and antiviral agents
Since SARS-CoV-2 emerged as the cause of the coronavirus disease 2019 (COVID-19) outbreak in Wuhan, China, it has achieved pandemic status, infecting over 6.59 million people and killing nearly 400,000 to date.
The World Health Organization has declared the pandemic a global public health emergency, and scientists are working around the clock to develop a vaccine.
Since a vaccine may not be available for at least a year, researchers are also urgently trying to develop effective antiviral agents, but, according to McInerney and the team, progress so far has been unremarkable, and no drugs have yet reached late phase clinical trials.
Once antiviral or antibody therapies do become available, they will be used to protect at-risk individuals and make it safer for people who have not yet been infected to exit lockdowns.
The RBD is an attractive target
As the part of the spike protein that binds to ACE2, the RBD is an appealing target for neutralization of SARS-CoV-2, and many conventional monoclonal antibodies that target this domain have already been isolated from recovered patients.
However, McInerney and colleagues say camelid-derived nanobodies offer several advantages over these conventional agents, since although they are much smaller, they have a similar affinity and specificity, while also being much easier to clone, express and manipulate.
In addition, “they are readily expressed in bacteria in large quantities and show high thermal stability and solubility, making them easily scalable and extremely cost-effective,” says the team.
Furthermore, these camelid-derived nanobodies can easily be humanized for application in humans using protocols that are already available.
What has the current study found?
Now, McInerney and team have shown that the alpaca-derived Ty1 nanobody binds with high affinity to the RBD on SARS-CoV-2 spike protein and potently neutralizes the virus.
This binding of the nanobody to RBD interrupted its interaction with ACE2, and the researchers determined that it was this interference that was responsible for neutralizing the virus.
The researchers say two conformations of the RBD on the spike protein have previously been observed in the stabilized trimer; one confirmation where ACE2 can access one RBD, but the other two RBDs cannot and another conformation where ACE2 can access all three domains.
Referring to the current study, the team says “A cryo-electron microscopy structure of the bound complex at 2.9 Å resolution reveals that the nanobody (Ty1) binds to an epitope on the RBD accessible in both the ‘up’ and ‘down’ conformations and that Ty1 sterically hinders RBD-ACE2 binding.”
The researchers hope TY1 can be investigated as a candidate SARS-CoV2 antiviral
The researchers add that the ability to produce Ty1 in high quantities recombinantly makes the nanobody an ideal candidate as a widely-accessible, low-cost, scalable antiviral against SARS-CoV-2.
Furthermore, “we provide the amino acid sequence, encouraging direct exploitation as such,” said McInerney and colleagues. “Based on our work, we hope that Ty1 can be investigated as a candidate for antiviral therapy,” they conclude.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.