New Nanobodies Block Coronavirus Infection, Locks Spikes Into 'Inactive' Mode

Infections from SARS-CoV-2 are rising worldwide with unimaginable destructive power, creating serious economic strife, a seemingly-endless loss of life, and growing health costs.

However, a new set of synthetic nanobodies successfully disrupted this binding process, effectively neutralizing the virus, according to a recent study shared on a pre-print blog. What's more, some of the nanobodies are robust enough for aerosol-based applications — opening the door for a widely-deployable agent to prevent COVID-19 illness.

You could say we've found a way to muzzle the novel coronavirus.

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Nanobodies lock coronavirus spikes into 'inactive' mode

So far we've learned how the virus infects human cells, namely, via an interaction between a Spike protein and the human host cell receptor called angiotensin-converting enzyme 2 (ACE2).

The coronavirus associated with causing COVID-19 illness makes its way into human host cells using its Spike protein and a host cell receptor, but new synthetic nanobodies substantially disrupt interactions between the coronavirus' Spike and the human host cell receptor, according to the study.

Without this connection, between the Spike protein and the ACE2, the coronavirus can't move forward with infection. When this interaction is disrupted, we see the means of viral entry neutralized, according to the study. This is why the scientists developed single-domain antibodies (nanobodies) capable of disrupting this crucial interaction between the virus and human host cells.

Manufacturing nanobodies to fight the coronavirus

While they screened a yeast surfaced-displayed library of synthetic nanobody sequences, the scientists found a group of nanobodies capable of binding to several epitopes on Spike and block ACE2 interactions, via a pair of unique mechanisms.

The first, called cryogenic electron microscopy (cryo-EM), which showed an exceptionally stable nanobody — Nb6. This binds (or converts) the coronavirus Spike protein into a fully-inactive conformation — with each receptor-binding domain (RBD) locked into its inaccessible down-state.

With the Spike protein in a down-state — like a key too short to extend into a locking mechanism — this makes the coronavirus unable to bind with ACE2 in human cells.

Second nanobody mechanism robust, 'widely-deployable'

Another mechanism — an affinity maturation and structure-guided design of multivalency — created a trivalent nanobody called mNb6-tri, featuring femtomolar affinity for the coronavirus Spike, and picomolar neutralization of the virus.

Notably, this second mechanism (mNb6-tri) remains stable and functional despite heat treatment, lyophilization, and aerosolization. In other words, it's robust. These robust qualities mean the second coronavirus-neutralizing nanobody type may be delivered via aerosol, firing it directly into the airway epithelia (tissues that line the human airways, like the throat and lungs).

This is significant because it could promise the development of a widely-deployable, patient-friendly preventative, or early-infection agent that could help to curb the worst pandemic in a century.

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