Scientists have developed novel, computer-designed proteins that can successfully identify and disable the virus responsible for COVID-19. These custom-built molecules, crafted from the ground up in the laboratory, show potent antiviral activity by tightly binding to the SARS-CoV-2 spike protein, effectively preventing it from infecting human cells. The research demonstrates a powerful new strategy for creating both antiviral therapeutics and rapid diagnostic tools.
The innovative approach, pioneered by researchers at the University of Washington School of Medicine’s Institute for Protein Design, harnesses computational power to create synthetic proteins that are smaller, more stable, and easier to produce than the monoclonal antibodies currently used to treat COVID-19. By precisely engineering these molecules to attach to the virus’s infection machinery, scientists have created binders that are, in some cases, six times more potent than the most effective antibodies. This breakthrough paves the way for a new class of antiviral drugs and sensitive biosensors that could be adapted to combat a wide range of viral threats.
Computational Design Creates Potent Antivirals
Researchers used sophisticated software to generate entirely new proteins, a method known as de novo design. The process began with designing over two million candidate proteins that were predicted to bind to the SARS-CoV-2 spike protein, the key component the virus uses to enter human cells by latching onto the ACE2 receptor. From this vast digital library, the team produced and physically tested more than 118,000 of the most promising designs to identify those with the strongest binding affinity.
The goal was to create a molecule that could perfectly conform to the spike protein’s receptor-binding domain, blocking its ability to interact with human cells. This computational approach allows for incredible precision, essentially building the antiviral protein atom by atom to achieve an optimal fit. The most successful candidate identified, a miniprotein named LCB1, demonstrated an exceptionally strong bond to the spike protein. In laboratory tests using lab-grown human cells, LCB1 effectively neutralized the virus, showing protective action that rivaled the best-known monoclonal antibodies.
A significant advantage of these synthetic proteins is their stability. Unlike natural antibodies, which are delicate and often require constant refrigeration to remain effective, these designed molecules are far more robust. This durability could eliminate the need for a cold chain, making it possible to produce, transport, and store potential therapeutics far more easily and affordably. This feature is particularly crucial for deploying antiviral treatments in remote or low-resource settings around the world.
A Two-Pronged Molecular Strategy
The scientific team pursued two distinct but related strategies to achieve their results. The first method involved taking a key segment of the human ACE2 receptor—the natural target of the virus—and incorporating it into various small, stable protein scaffolds. This essentially used the virus’s own target as a blueprint to create a decoy that could intercept and bind to it.
The second, and ultimately more successful, approach was to design completely synthetic proteins from scratch. This method provided greater freedom to optimize the molecule for both binding strength and stability, unconstrained by the structures of naturally occurring proteins. The LCB1 antiviral emerged from this second strategy. By designing a molecule perfectly tailored to the viral spike, the researchers created an inhibitor that is not only highly potent but also small and simple enough to be produced at large scale with relative ease, potentially in microbial production systems rather than more complex mammalian cell cultures used for antibodies.
Mechanism of Viral Neutralization
Coronaviruses are characterized by the crown of spike proteins that stud their outer surface. These spikes are precision tools for infection, specifically shaped to recognize and attach to receptors on the surface of a host’s cells. For SARS-CoV-2, this process is the critical first step in its life cycle, allowing the virus to breach the cell membrane and release its genetic material inside.
The engineered proteins work by physically obstructing this mechanism. Their structure includes a binding surface that is a near-perfect mirror image of a key region on the viral spike. When the protein is introduced, it seeks out and locks onto the spike, covering the parts that would normally attach to a human cell. This binding action acts as a molecular shield, effectively disarming the virus. With its infection machinery jammed, the virus is unable to initiate an infection and is left vulnerable to clearance by the body’s immune system. This direct interference with viral entry is a powerful method for preventing or treating an infection before it can take hold.
From Therapeutics to Advanced Diagnostics
Beyond their therapeutic potential, these engineered proteins serve as the foundation for a new generation of diagnostic biosensors. The same principles used to design virus-neutralizing molecules were applied to create sensors that can detect the presence of viral components with high specificity and sensitivity. The researchers adapted the technology to build protein-based devices that emit light when they successfully bind to either the SARS-CoV-2 spike protein or the antibodies a person produces in response to an infection.
When mixed with a sample, such as fluid from a nasal swab or a drop of blood, these biosensors glow within minutes if their target molecule is present. This approach avoids the need for RT-PCR, the current standard for diagnosing COVID-19, which requires complex lab equipment, specialized reagents, and trained personnel. The new biosensors are being optimized for use without any laboratory instruments or refrigeration, potentially leading to rapid, reliable tests that can be deployed widely at points of care, such as clinics, airports, or even at home.
Future of Designed Protein Technologies
The successful creation of these antiviral and diagnostic proteins marks a significant milestone in computational biology and medicine. The platform developed by the researchers is highly adaptable and could be rapidly modified to address future viral threats. As new pathogens emerge, their key surface proteins could be sequenced and analyzed, allowing scientists to quickly design and test new custom-made inhibitors and sensors.
This work is part of a broader effort at the Institute for Protein Design to create a wide range of novel proteins for human benefit, from vaccines to catalysts for clean energy. A different nanoparticle technology from the same institute has already been used in a COVID-19 vaccine, now called SKYCovione, which has been authorized in the United Kingdom and South Korea. The ability to move from a digital concept on a computer to a physical molecule with a desired biological function in a matter of months demonstrates a transformative shift in how humanity can respond to pandemics and other health crises.