As the fight against COVID-19 progresses and the virus continues to mutate, vaccines and various monoclonal antibody drugs are losing some steam. That adds urgency to a strategy to prevent and treat the disease that could theoretically stop all variants of SARS-CoV-2. The idea is to flood the body with proteins that mimic the receptor for angiotensin-converting enzyme 2 (ACE2), the cell-surface protein that SARS-CoV-2 uses to enter cells. These decoys would bind to the virus’s spike protein and disarm it. The molecules could protect people from becoming infected and help COVID-19 patients clear the virus from their bodies.
An ACE2 lure recently completed initial human safety testing, and trials of other lure designs are expected to launch soon. A new preprint also shows that giving mice a gene encoding a decoy may provide long-term protection, a strategy that could help millions of immunocompromised patients who are unable to mount a robust immune response to vaccines. Success against COVID-19 could also spur efforts to develop lures against other infectious diseases ranging from influenza to Ebola.
“Are [compounds] it could be a game changer,” says Erik Procko, a biochemist at Cyrus Biotechnology, a Seattle-based biotech company working to commercialize lures to combat COVID-19 and human cytomegalovirus.
Research teams have explored the idea of decoy receptors for HIV and some other viruses for many years, but have made little clinical progress for a number of reasons. The strategy was investigated during the severe acute respiratory syndrome (SARS) outbreak 2 decades ago. In 2005, Josef Penninger, a molecular biologist then at the Institute for Molecular Biology in Vienna, and his colleagues discovered that the SARS coronavirus, a relative of SARS-CoV-2, 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 only the part of ACE2 that protrudes above the cell surface and is exposed to the virus. They showed that the decoy partially protected the mice from lung failure and other symptoms caused by ACE2 dysfunction. But they didn’t have time to test their lure on SARS animals before the original outbreak died down.
When SARS-CoV-2 made its appearance in late 2019, Penninger, now at the University of British Columbia, Vancouver, and his colleagues got back on the ball. After his team and others showed that ACE2 was the target of SARS-CoV-2 as well, they took their lures 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.
He arranged small human trials of an injected form of the ACE2 decoy. The protein was shown to be safe, notably not triggering blood pressure abnormalities or other metabolic problems, but it had little effect in reducing the severity of COVID-19. Penninger argues that this was likely because it was given to patients relatively late in their disease. The company is now pursuing the inhaled variety and completed an initial human safety study last year. Although the company has yet to release the results, Penninger, who has seen the data, says: “There’s no reason not to change [the compound] Go ahead”, either as a treatment if given early enough, or as a prophylactic.
Other groups also took advantage of the decoy idea, creating novel versions designed to last longer in the body and bind more tightly to the virus’s spike protein, reducing the dose needed. 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 in cell membranes. Tests on cells and mice challenged with SARS-CoV-2 showed that 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 start human safety trials 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 to increase the potency of antibody-based drugs, Procko and his colleagues linked the so-called Fc region of a human antibody to an ACE2 decoy. The Fc region caused it to form pairs, which bind more strongly 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 in protecting mice from SARS-CoV-2 that Procko left the UI and joined Cyrus, who plans to launch a clinical trial of the compound.
Now, Nathaniel Landau, a microbiologist at New York University (NYU), and colleagues have published results showing a similar lure to Procko’s mice protected against infection by many of the latest Omicron virus variants, which have evolved to evade antibody drugs that work against the original SARS-CoV-2 virus. The researchers believe that lures, by contrast, are unlikely to lose their potency. If SARS-CoV-2 evolves to prevent decoys from binding, the virus’s own ability to bind to and infect cells will likely be affected as well. “It puts viruses in checkmate,” says Landau, who published the findings in a Jan. 2 preprint on bioRxiv.
The NYU team also went a step further. The body would quickly break down a dose of inhaled or injected lures. But in a second preprint published Jan. 12 in bioRxiv, the researchers reported that they had packaged a gene for the decoy into viruses commonly used as “vectors” to deliver disease-treating genes. By injecting a small dose into mice, they showed that the vectors infected muscle cells, causing them to produce the decoy, which then protected the animals from infection for up to 2 months.
Landau acknowledges that gene therapy targeting SARS-CoV-2 in healthy people is not likely to be approved by regulators. However, he adds, “it could be extremely useful for immunocompromised people who are unable to mount an effective immune response” to either natural infection or a vaccine. Guangping Gao, a gene therapy expert at the University of Massachusetts Chan School of Medicine, agrees, saying, “This project has great potential.” Others point out, however, that the immune system often fights off viral vectors, which could limit the effectiveness of the approach in preventing COVID-19.
However they are delivered, using decoys to thwart SARS-CoV-2 could be just the beginning. Baker’s University of Washington 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 lures to combat mpox, influenza, HIV and ebola. “This could be the cutting edge of pandemic prevention,” she says. “All we need is the structure [of a viral target] design against”.
Source: news.google.com