Biochemist Longxing Cao is working with colleagues at the University of Washington on promising research to disable infectious coronavirus in a person's nose.
This may sounds like science fiction, but several research groups are already working on such trickster coronavirus drugs, with some candidates close to clinical trials and possibly even becoming available late this year. The teams began working on them when the pandemic arrived, and continued in lockdown.
When the pandemic first hit and the state of California issued a lockdown order on March 16, postdoctoral researchers Anum and Jeff Glasgow found themselves stuck at home with nothing to do. The two scientists who study bioengineering felt that they were well equipped to research molecular ways of disabling coronavirus's cell-penetrating spike protein, but they could no longer come to their labs at the University of California San Francisco.
"We were upset that no one put us in the game," says Anum Glasgow. "We have a lot of experience between us doing these types of projects so we wanted to contribute." But they still had computers so they began modeling the potential virus-disabling proteins in silico using Robetta, special software for designing and modeling protein structures, developed and maintained by University of Washington biochemist David Baker and his lab.
"We saw some imperfections in that lock and key and we created something better. We made a 10 times tighter adhesive."
The SARS-CoV-2 virus that causes Covid-19 uses its surface spike protein to bind on to a specific receptor on human cells called ACE2. Unfortunately for humans, the spike protein's molecular shape fits the ACE2 receptor like a well-cut key, making it very successful at breaking into our cells. But if one could design a molecular ACE2-mimic to "trick" the virus into latching onto it instead, the virus would no longer be able to enter cells. Scientists call such mimics receptor traps or inhibitors, or blockers. "It would block the adhesive part of the virus that binds to human cells," explains Jim Wells, professor of pharmaceutical chemistry at UCSF, whose lab took part in designing the ACE2-receptor mimic, working with the Glasgows and other colleagues.
The idea of disabling infectious or inflammatory agents by tricking them into binding to the targets' molecular look-alikes is something scientists have tried with other diseases. The anti-inflammatory drugs commonly used to treat autoimmune conditions, including rheumatoid arthritis, Crohn's disease and ulcerative colitis, rely on conceptually similar molecular mechanisms. Called TNF blockers, these drugs block the activity of the inflammatory cytokines, molecules that promote inflammation. "One of the biggest selling drugs in the world is a receptor trap," says Jeff Glasgow. "It acts as a receptor decoy. There's a TNF receptor that traps the cytokine."
In the recent past, scientists also pondered a similar look-alike approach to treating urinary tract infections, which are often caused by a pathogenic strain of Escherichia coli. An E. coli bacterium resembles a squid with protruding filaments equipped with proteins that can change their shape to form hooks, used to hang onto specific sugar molecules called ligands, which are present on the surface of the epithelial cells lining the urinary tract.
A recent study found that a sugar-like compound that's structurally similar to that ligand can play a similar trick on the E. Coli. When administered in in sufficient amounts, the compound hooks the bacteria on, which is then excreted out of the body with urine. The "trickster" method had been also tried against the HIV virus, but it wasn't very effective because HIV has a high mutation rate and multiple ways of entering human cells.
But the coronavirus spike protein's shape is more stable. And while it has a strong affinity for the ACE2 receptors, its natural binding to these receptors isn't perfect, which allowed the UCSF researchers to design a mimic with a better grip. "We saw some imperfections in that lock and key and we created something better," says Wells. "We made a 10 times tighter adhesive." The team demonstrated that their traps neutralized SARS-CoV-2 in lab experiments and published their study in the Proceedings of the National Academy of Sciences.
Baker, who is the director of the Institute for Protein Design at the University of Washington, was also devising ACE2 look-alikes with his team. Only unlike the UCSF team, they didn't perfect the virus-receptor lock and key combo, but instead designed their mimics from scratch. Using Robetta, they digitally modeled over two million proteins, zeroed-in on over 100,000 potential candidates and identified a handful with a strong promise of blocking SARS-CoV-2, testing them against the virus in human cells. Their design of the miniprotein inhibitors was published in the journal Science.
Biochemist David Baker, pictured in his lab at the University of Washington.
UW
The concept of the ACE2 receptor mimics is somewhat similar to the antibody plasma, but better, the teams explain. Antibodies don't always coat all of the virus's spike proteins and sometimes don't bind perfectly. By contrast, the ACE2 mimics directly compete with the virus's entry mechanism. ACE2 mimics are also easier and cheaper to make, researchers say.
Antibodies, which are long protein chains, must be grown inside mammalian cells, which is a slow and costly process. As drugs, antibody cocktails must be kept refrigerated. On the contrary, proteins that mimic ACE2 receptors are smaller and can be produced by bacteria easily and inexpensively. Designed to specs, these proteins don't need refrigeration and are easy to store. "We designed them to be very stable," says Baker. "Our computation design tries to come up with the stable proteins that have the desired functions."
That stability may allow the team to create an inhaler drug rather than an intravenous one, which would be another advantage over the antibody plasma, given via an IV. The team envisions people spraying the miniprotein solution into their nose, creating a protecting coating that would disable the inhaled virus. "The infection starts from your respiratory system, from your nose," explains Longxing Cao, the study's co-author—so a nasal spray would be a natural way to administer it. "So that you can have it like a layer, similar to a mask."
As the virus evolves, new variants are arising. But the teams think that their ACE2 protein mimics should work on the new variants too for several reasons. "Since the new SARS-CoV-2 variants still use ACE2 for their cell entry, they will likely still be susceptible to ACE2-based traps," Glasgow says.
Cao explains that their approach should work too because most of the mutations happen outside the ACE2 binding region. Plus, they are building multiple binders that can bind to an array of the coronavirus variants. "Our binder can still bind with most of the variants and we are trying to make one protein that could inhibit all the future escape variants," he says.
Baker and Cao hope that their miniproteins may be available to patients later this year. But besides getting the medicine out to patients, this approach will allow researchers to test the computer-modeled mimics end-to-end with an unprecedented speed. That would give humans a leg up in future pandemics or zoonotic disease outbreaks, which remain an increasingly pressing threat due to human activity and climate change.
"That's what we are focused on right now—understanding what we have learned from this pandemic to improve our design methods," says Baker. "So that we should be able to obtain binders like these very quickly when a new pandemic threat is identified."
Thanks to safety cautions from the COVID-19 pandemic, a strain of influenza has been completely eliminated.
The flu shot, explained
Influenza viruses type A and B are responsible for the majority of human illnesses and the flu season.
Centers for Disease Control
For more than a decade, flu shots have protected against two types of the influenza virus–type A and type B. While there are four different strains of influenza in existence (A, B, C, and D), only strains A, B, and C are capable of infecting humans, and only A and B cause pandemics. In other words, if you catch the flu during flu season, you’re most likely sick with flu type A or B.
Flu vaccines contain inactivated—or dead—influenza virus. These inactivated viruses can’t cause sickness in humans, but when administered as part of a vaccine, they teach a person’s immune system to recognize and kill those viruses when they’re encountered in the wild.
Each spring, a panel of experts gives a recommendation to the US Food and Drug Administration on which strains of each flu type to include in that year’s flu vaccine, depending on what surveillance data says is circulating and what they believe is likely to cause the most illness during the upcoming flu season. For the past decade, Americans have had access to vaccines that provide protection against two strains of influenza A and two lineages of influenza B, known as the Victoria lineage and the Yamagata lineage. But this year, the seasonal flu shot won’t include the Yamagata strain, because the Yamagata strain is no longer circulating among humans.
How Yamagata Disappeared
Flu surveillance data from the Global Initiative on Sharing All Influenza Data (GISAID) shows that the Yamagata lineage of flu type B has not been sequenced since April 2020.
Nature
Experts believe that the Yamagata lineage had already been in decline before the pandemic hit, likely because the strain was naturally less capable of infecting large numbers of people compared to the other strains. When the COVID-19 pandemic hit, the resulting safety precautions such as social distancing, isolating, hand-washing, and masking were enough to drive the virus into extinction completely.
Because the strain hasn’t been circulating since 2020, the FDA elected to remove the Yamagata strain from the seasonal flu vaccine. This will mark the first time since 2012 that the annual flu shot will be trivalent (three-component) rather than quadrivalent (four-component).
Should I still get the flu shot?
The flu shot will protect against fewer strains this year—but that doesn’t mean we should skip it. Influenza places a substantial health burden on the United States every year, responsible for hundreds of thousands of hospitalizations and tens of thousands of deaths. The flu shot has been shown to prevent millions of illnesses each year (more than six million during the 2022-2023 season). And while it’s still possible to catch the flu after getting the flu shot, studies show that people are far less likely to be hospitalized or die when they’re vaccinated.
Another unexpected benefit of dropping the Yamagata strain from the seasonal vaccine? This will possibly make production of the flu vaccine faster, and enable manufacturers to make more vaccines, helping countries who have a flu vaccine shortage and potentially saving millions more lives.
Founder Lewis Hornby and his grandmother Pat, sampling Jelly Drops—an edible gummy containing water and life-saving electrolytes.
When Lewis Hornby visited his grandmother at her nursing home afterward, he learned that dehydration especially affects people with dementia, as they often don’t feel thirst cues at all, or may not recognize how to use cups correctly. But while dementia patients often don’t remember to drink water, it seemed to Hornby that they had less problem remembering to eat, particularly candy.
Where people with dementia often forget to drink water, they're more likely to pick up a colorful snack, Hornby found. alzheimers.org.uk
Hornby wanted to create a solution for elderly people who struggled keeping their fluid intake up. He spent the next eighteen months researching and designing a solution and securing funding for his project. In 2019, Hornby won a sizable grant from the Alzheimer’s Society, a UK-based care and research charity for people with dementia and their caregivers. Together, through the charity’s Accelerator Program, they created a bite-sized, sugar-free, edible jelly drop that looked and tasted like candy. The candy, called Jelly Drops, contained 95% water and electrolytes—important minerals that are often lost during dehydration. The final product launched in 2020—and was an immediate success. The drops were able to provide extra hydration to the elderly, as well as help keep dementia patients safe, since dehydration commonly leads to confusion, hospitalization, and sometimes even death.
Not only did Jelly Drops quickly become a favorite snack among dementia patients in the UK, but they were able to provide an additional boost of hydration to hospital workers during the pandemic. In NHS coronavirus hospital wards, patients infected with the virus were regularly given Jelly Drops to keep their fluid levels normal—and staff members snacked on them as well, since long shifts and personal protective equipment (PPE) they were required to wear often left them feeling parched.
In April 2022, Jelly Drops launched in the United States. The company continues to donate 1% of its profits to help fund Alzheimer’s research.