Protein decoys for viruses may battle COVID-19 and more

As the fight against COVID-19 wears on and the virus continues to mutate, vaccines and several monoclonal antibody drugs are losing some of their punch. That’s added urgency to a strategy for preventing and treating the disease that, in theory, could stop all variants of SARS-CoV-2. The idea is to flood the body with proteins that mimic the angiotensin-converting enzyme 2 (ACE2) receptor, the cell-surface protein that SARS-CoV-2 uses to gain entry into cells. These decoys would bind to the virus’ spike protein, disarming it. The molecules might both protect people from getting infected and help COVID-19 patients clear the virus from the body.

One ACE2 decoy recently completed initial safety trials in humans, and trials of other decoy designs are expected to launch soon. A new preprint also shows that giving mice a gene coding for a decoy can provide long-term protection, a strategy that might help millions of immune-compromised patients who are unable to mount a robust immune response to vaccines. Success against COVID-19 might also boost efforts to develop decoys against other infectious diseases ranging from influenza to Ebola.

“These [compounds] could be a game changer,” says Erik Procko, a biochemist at Cyrus Biotechnology, a Seattle-based biotech company working to commercialize decoys to fight COVID-19 and human cytomegalovirus.

Research teams have for many years explored the idea of decoy receptors for HIV and a few others viruses but made little clinical headway for various reasons. The strategy was investigated during the outbreak of severe acute respiratory syndrome (SARS) 2 decades ago. In 2005, Josef Penninger, a molecular biologist then at the Institute of Molecular Biology in Vienna, and his colleagues discovered that the SARS coronavirus, a SARS-CoV-2 relative, binds to ACE2 in mice. The receptor protein normally helps regulate blood pressure and other metabolic processes, but it can also contribute to conditions such as lung failure.

Penninger’s team synthesized just the part of ACE2 that protrudes above the cell surface and is exposed to the virus. They showed that the decoy partially protected mice from lung failure and other symptoms driven by ACE2 dysfunction. But they didn’t have time to test their decoy on animals with SARS before the original outbreak fizzled out.

When SARS-CoV-2 made its appearance in late 2019, Penninger, now at the University of British Columbia, Vancouver, and his colleagues jumped back in. After his team and others showed that ACE2 was the target for SARS-CoV-2 as well, they pulled their decoys off the shelf. The molecules proved effective against SARS-CoV-2 infection in cell cultures and in mice, and Penninger licensed the strategy to APEIRON Biologics, an Austrian company he had previously founded.

It organized small human trials of an injected form of the ACE2 decoy. The protein was shown to be safe—notably it did not trigger blood pressure anomalies or other metabolic issues—but it had little effect in reducing the severity of COVID-19. Penninger argues this was likely because it was given to patients relatively late in their disease. The company is now pursuing the inhaled variety and last year concluded an initial safety study in humans. Though the company has yet to publish the results, Penninger, who has seen the data, says, “There’s no reason not to move [the compound] forward,” as either a treatment if given early enough, or as a prophylactic.

Other groups also jumped on the decoy idea, creating novel versions designed to last longer in the body and bind more tightly to the virus’ spike protein, reducing the needed dose. In 2020, for example, researchers led by David Baker, a protein designer at the University of Washington (UW), Seattle, engineered a decoy made up of three copies of the ACE2-binding region, matching the three-part symmetry of ACE2 on cell membranes. Tests on cells and mice challenged with SARS-CoV-2 showed the decoys were highly effective at blocking infection. Baker’s team has since partnered with a South Korean startup called SK Bioscience, which says it plans to begin human safety tests later this year.

Procko, a former postdoc in Baker’s lab who moved to the University of Illinois (UI), Urbana-Champaign, in 2014, took a different tack. Following a long-used strategy for increasing the potency of antibody-based drugs, Procko and his colleagues linked the so-called Fc region from a human antibody to an ACE2 decoy. The Fc region caused it to form pairs, which bind more tightly to the spike protein. Procko and his colleagues also mutated their decoys to further increase their binding strength and prevent them from cutting other proteins, part of ACE2’s natural function. The changes proved so effective at protecting mice from SARS-CoV-2 that Procko left the UI and joined Cyrus, which plans to launch a clinical trial of the compound.

Now, Nathaniel Landau, a microbiologist at New York University (NYU), and his colleagues have posted results showing a decoy similar to Procko’s protected mice against infection by many of the latest Omicron variants of the virus, which have evolved to evade antibody drugs that work against the original SARS-CoV-2 virus. Researchers think the decoys, in contrast, are unlikely to lose their potency. If SARS-CoV-2 does evolve to prevent decoys from binding, the virus’ own ability to bind to and infect cells will probably suffer as well. “It puts the viruses in checkmate,” says Landau, who published the findings in a 2 January preprint on bioRxiv.

The NYU team also went a step further. The body would quickly break down a dose of inhaled or injected decoys. But in a second preprint posted on 12 January on bioRxiv the researchers reported they’d packaged a gene for the decoy into viruses commonly used as “vectors” to deliver disease-treating genes. Injecting a small dose into mice, they showed the vectors infected muscle cells, causing them to churn out the decoy, which then protected the animals from infection for up to 2 months.

Landau acknowledges that regulators aren’t likely to approve gene therapy targeting SARS-CoV-2 in otherwise healthy people. However, he adds, “It could be extremely useful for immunocompromised people who can’t generate an effective immune response” to either a natural infection or a vaccine. Guangping Gao, a gene therapy expert at the University of Massachusetts Chan Medical School, agrees, saying, “This project has great potential.” Others note, however, that the immune system often fights off viral vectors, which could limit the effectiveness of the approach for preventing COVID-19.

However they’re delivered, using decoys to stymie SARS-CoV-2 could be just the beginning. Baker’s UW colleague Lauren Carter, a pharmaceutical bioengineer at the university’s Institute for Protein Design, notes that Baker’s group and others are already designing new or improved decoys to fight mpox, influenza, HIV, and Ebola. “This could be the avant-garde of pandemic prevention,” she says. “All we need is the structure [of a viral target] to design against.”