Preexisting drug shows promise in fight against COVID-19

First appearing in late 2019 in Wuhan City, China, the SARS-CoV-2 virus continues to cause sickness and death across the globe. Researchers and scientists have been looking at multiple solutions to treat COVID-19, including repurposing approved pharmaceutical drugs. This research points to very promising treatment options.

A team of researchers at the Pritzker School of Molecular Engineering (PME) at the University of Chicago used state-of-the-art computer simulations to identify a preexisting drug that could fast-track a solution to this worldwide pandemic.

Their findings appear in the paper, “Molecular Characterization of Ebselen Binding Activity to SARS-CoV-2 Main 4 Protease,” which was published on August 14 in the journal Science Advances.

Mpro Versus Ebselen

Early in February, concerned by the rapid progress of the pandemic, Professor Juan de Pablo and his students used their molecular modeling expertise to help find a treatment against the disease. They were not the only ones. Other groups around the world were beginning to use supercomputers to rapidly screen thousands of existing compounds for potential use against the SARS-CoV-2 virus.

“By virtue of the large number of compounds considered in high throughput screens, those calculations must necessarily involve a number of simplifications, and the results must then be evaluated using experiments and more refined calculations,” de Pablo explained.

Researchers first focused on finding a weakness in the virus to target. They chose its main protease: Mpro. Mpro is a key coronavirus enzyme that plays a central role in the virus’ life cycle. It facilitates the virus’ ability to transcribe its RNA and replicate its genome within the host cell.

A pharmaceutical drug that shows promise as a weapon against Mpro is Ebselen. Ebselen is a chemical compound with anti-viral, anti-inflammatory, anti-oxidative, bactericidal, and cell-protective properties. Ebselen is used to treat multiple diseases, including bipolar disorders and hearing loss. In combination with silver, Ebselen treats five clinically difficult-to-manage antibiotic-resistant Gram-negative bacteria. Several clinical trials have proven its safety for use in humans.

How It Works

de Pablo and his students set out to develop detailed models of the enzyme and the drug. Using those models and sophisticated supercomputer simulations, they discovered that the small Ebselen molecule is able to decrease Mpro’s activity in two different ways.

“In addition to binding at the catalytic site of the enzyme, Ebselen also binds strongly to a distant site, which interferes with the enzyme’s catalytic function by relying on a mechanism in which information is carried from one region of a large molecule to another region far away from it through subtle structural reorganizations,” de Pablo says.

That finding was particularly important because it helped explain Ebselen’s potential efficacy as a repurposed drug, and it revealed a new vulnerability in the virus that was previously not known and that could be use useful in developing new therapeutic strategies against COVID-19.

By working around the clock, the team completed their work in just over two months and submitted their manuscript to public research archives in April for others to consider.

Drug Development Potential

The research team’s discovery of two binding sites looks promising for Ebselen to be a new drug lead for the design and development of new Mpro inhibitors and COVID-19 treatment. Motivated by their findings, de Pablo and his student are quick to point out that much work is yet to be done.

“The main protease is one of many proteins in the virus that could be targeted with existing, repurposed drugs, and there are thousands of compounds to be considered,” de Pablo says. “We are systematically investigating each of the proteins involved in the virus function and investigating their vulnerabilities and their responses to a wide range of drugs.”

de Pablo and his team will soon release a comprehensive study of the RBD/ACE2 complex from the virus and another drug that offers promise to interfere with the binding of the virus to cells.

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More information: Molecular Characterization of Ebselen Binding Activity to SARS-CoV-2 Main Protease, arXiv:2005.09805 [q-bio.BM] arxiv.org/abs/2005.09805

Science Advances  14 Aug 2020: DOI: 10.1126/sciadv.abd0345 , advances.sciencemag.org/conten … 08/14/sciadv.abd0345

https://medicalxpress.com/news/2020-08-preexisting-drug-covid-.html

Saliva-based coronavirus test funded by NBA, NBPA gets FDA emergency OK

The U.S. Food and Drug Administration issued an emergency authorization on Saturday allowing public use of a saliva-based test for the coronavirus developed at Yale University and funded by the NBA and the National Basketball Players Association.

The test, known as SalivaDirect, is designed for widespread public screening. The cost per sample could be as low as about $4, though the cost to consumers will likely be higher than that — perhaps around $15 or $20 in some cases, according to expert sources.

Yale administered the saliva test to a group that included NBA players and staff in the lead-up to the league’s return to play and compared results to the nasal swab tests the same group took. The results almost universally matched, according to published research that has not yet been peer-reviewed.

The leading coronavirus saliva test, developed at a Rutgers University lab and given the same permission by the FDA in mid-April, costs individual consumers up to $150 — though that can be reduced to $60 or $70 in some circumstances, said Andrew Brooks, an associate professor at Rutgers and chief operating officer of RUCDR Infinite Biologics, the lab behind the test. The Rutgers test can be taken at home and returns results in 24 to 48 hours.

Several NBA teams used the Rutgers test in June, and Brooks said several sports teams are still using it. Those teams fly saliva samples to one of several labs — including the Rutgers lab in New Jersey — approved for administering the test, which adds time and cost.

The Yale test funded by the league and players’ union is simple enough to be used by labs everywhere provided they go through required accreditation processes, said Nathan Grubaugh, an assistant professor of epidemiology at Yale and one of two senior authors, along with Anne Wyllie, an associate research scientist in epidemiology, behind the saliva studies. Consumers dribble saliva into a narrow tube. Depending on the proximity of the lab, consumers could get results back within a few hours — and definitely within 24 hours, Grubaugh said.

The Yale test removes one cumbersome and expensive step — the extraction of RNA from samples — that is a core part of nasal swab tests and the Rutgers test. Scientists warned early in the pandemic about supply chain bottlenecks and shortages in equipment required to extract RNA.

Extraction makes for a clearer and more certain result, according to both Brooks and Grubaugh.

“(The Yale test) loses a little bit of sensitivity, but what we gain is speed and that it should be up to 10 times cheaper,” Grubaugh said. The Yale test replaces the extraction step with the introduction of a reagent — chemicals mixed with the saliva sample — and a short heating process that releases the virus genome. The team found successful results using reagents that are commonly available, meaning labs everywhere could implement the Yale protocol, Grubaugh said.

“My goal is not to test athletes,” Grubaugh said. “That’s not my target population. My target population is everybody. There were concerns about partnering with the NBA when all these other people need testing. But the simple answer ended up being the NBA was going to do all this testing anyway, so why not partner with them and try to create something for everyone?”

The NBA, Yale and the players’ association do not intend to take royalties from any use of the testing method, Grubaugh and others said. The NBA and union contributed more than $500,000 combined to fund the Yale work, sources told ESPN.

Andy Slavitt, the acting administrator of the Centers for Medicare and Medicaid Services during the Obama administration, circulated the Yale results among former FDA commissioners in hopes of guiding it to a faster emergency use approval, he and others said.

“I helped make sure the right people in the White House were aware of the importance of the test, and the rest took care of itself,” Slavitt told ESPN’s Adrian Wojnarowski. Slavitt has been part of a working group of virus specialists that includes several sports scientists and the NBA league office.

“My interest was to help get a low-cost scalable test that can be a game-changer across the country,” Slavitt said. “We didn’t get leadership from where we needed it, but it’s great to see the NBA emerge.”

The genesis of the Yale-NBA partnership happened in early April, when Grubaugh and the Yale team published preliminary research indicating saliva tests conducted on coronavirus patients and health care workers were as accurate as nasal swab tests. “That was a critically important paper,” said Martin Burke, a chemistry professor at the University of Illinois whose team developed a similar direct saliva test. “It was inspiring to us.”

Illinois is now administering its test to returning faculty and staff — tens of thousands of people. They intend to test people twice per week, Burke said.

When Yale released its initial findings in April, officials in the NBA league office and sports scientists across the league were calling labs and scouring literature for possible clues on how they might develop fast, cheap and easily accessible testing for players. League and team officials were also aware of the criticism they had received early in the pandemic for acquiring tests when they were in short supply and were eager to do something in the broader public interest.

One team official — Robby Sikka, vice president of basketball performance and technology for the Minnesota Timberwolves — came across the Yale paper and emailed Grubaugh.

“We had a lot of strange requests, but this one was at the top,” Grubaugh said. “I saw Timberwolves in the subject line and said, ‘What the heck?'”

The two connected. The research quickly reached the desk of NBA senior vice president David Weiss, the league’s point person for coronavirus response — including the formation of the bubble at the Walt Disney World Resort in Orlando.

“A lot of sports leagues and larger organizations were thinking, ‘OK, we’re shut down, so what can we do?'” Grubaugh said. “‘We are going to have to be testing our population — players — all the time if we want to play again. How can we do that?”‘

The Yale lab at the time did not have its own test; it had used previously existing tests to measure the accuracy of saliva testing. Sikka and the league pitched the idea of building one, and the NBA and players’ union offered to fund it.

“I was hesitant,” Grubaugh said. “We do research. We are not developers of diagnostics. But this was an opportunity. They were willing to fund it. This is a crazy time for everyone anyway. I studied mosquitoes before this.”

With players returning to team markets in April and May, the league put out a call for volunteers to take saliva tests — for the purpose of comparing results to the nasal swab tests the same group would also take. The results showed close to universal agreement between tests, according to Yale’s research.

Brooks, the Rutgers professor, expressed some skepticism about the scalability of the Yale/NBA test. That test still requires labs to purchase an expensive molecular testing machine. Labs administering the test will also be responsible for huge batches of data collection and storage, Brooks said. He also reiterated that RNA extraction is more precise.

“I get that everyone wants to do it more quickly and for a less expensive price, but there also has to be a level of responsibility,” Brooks said.

In the NBA’s campus in Orlando, the league is still using nasal swabs on players, coaches and staff.

The potential for rapid-return, cheap and easy-to-administer saliva tests may have implications for the structure of the 2020-21 NBA season, sources said. Any return to normalcy — teams traveling to 28 home markets, the presence of even some token number of fans to offset revenue losses — is dependent on testing becoming easily available. This could be one step, experts said.

Yale and the NBA have already spoken to a national lab company about using robotic technology to speed up the processing of tests, sources said. Both parties are interested in the potential of pool saliva testing — combining samples from several people and testing them together. (Any positive result would then require individual testing.)

“Through some miracle, this is working,” Grubaugh said. “It’s sensitive. It’s cheap. And now it’s getting approval. I’m not quite sure how we ended up here from April.”

https://www.espn.com/nba/story/_/id/29667299/fda-allowing-saliva-based-test-funded-nba

Baxter gets emergency authorization for kidney med during pandemic

Baxter (NYSE:BAX) +1.1% AH, says it received FDA emergency use authorization for Regiocit, a solution to be used in treatment of certain patients with acute kidney injury, a complication that has affected many COVID-19 patients.

Regiocit is authorized to be used as a replacement solution only in adult patients being treated with continuous renal replacement therapy and for whom regional citrate anticoagulation is appropriate during the Covid-19 pandemic

It’s in use in Europe and Asia, and a limited initial shipment will be available in the U.S. immediately.

https://seekingalpha.com/news/3605989-baxter-gets-emergency-authorization-for-regiocit-during-covidminus-19-pandemic

A disturbing reason so few buildings have windows that open

Over 200 scientists, including myself, signed a letter that was published in the journal Clinical Infectious Diseases on July 6 2020 saying that COVID is not only spread by touch and droplets sprayed from the mouth and nose but, importantly, via a third route, too.

The third infection pathway is in very tiny airborne particles of liquid and material, known as aerosols, that stay suspended in the air for a long time. If the virus attaches to these tiny particles, it can float on the air and spread much further. An effective way to reduce this spread is to purge the air containing those aerosols from rooms by simply opening the windows, as shown here. By opening a window to let the virus escape, the amount of it in a room can be reduced, leading to a lower risk of infection.

Three days after our letter was published in Clinical Infectious Diseases, the World Health Organization admitted that aerosol transmission can’t be ruled out, given the growing evidence of disease spread in poorly ventilated venues such as restaurants, nightclubs, and places of worship.

Aerosol spread was shown in late January in Guangzhou, China, where 10 people fell ill with the novel coronavirus after eating lunch in a fifth-floor restaurant without windows. The virus had probably been spread in aerosol form by an air conditioner—although the study has yet to be peer-reviewed.

To prevent COVID from spreading:

• Medical experts promote hand washing, protective clothing, cleaning surfaces, spatial distancing, fewer people in lifts, and the wearing of face masks—all practical and effective actions.
• Heating, ventilating, and cooling (HVAC) engineers recommend limiting the spread of the virus with expensive, high-efficiency particulate air and ultraviolet filters for climate-control systems in buildings that work well for those who can afford them.
• Architects, when looking at the impacts of COVID on buildings often deal with issues of social and physical distancing within buildings, and toy with the idea of the “end of tall buildings,” or the effect of the shift to home-working on the energy efficiency of our homes.

Very few of the above groups even mention the importance of simply opening windows, or the added benefits of the thermal, emotional, and sensual delight of a cooling breeze on the skin on a warm day. Or the relief of clean, fresh air pouring into a stuffy room.

Building designers today often don’t understand that they have been cheated by not being taught how to ventilate buildings naturally. Modern, fast, cheap design has three key drivers: one, the architectural fantasy that their main professional contribution to society is in sculptural art; two, what the building regulations require; and three, the limits imposed on designers by the almost universal use of flawed building simulation models that steer designers away from naturally ventilating buildings.

Conflict of interests

Building regulations are written largely by HVAC engineers, including in the US and the UK. HVAC engineers are typically paid according to the amount of HVAC equipment that goes into a building, which is a conflict of interest issue that needs to be addressed globally.

Given that engineers write the rules, it is hardly surprising that buildings are required to have ever more machinery installed in them to comply with those rules. No wonder architects now earn less than HVAC engineers, bricklayers, plumbers, and even scaffolders.

If you are sitting in an overheated, stuffy room, with windows that don’t open, or are finding it difficult to pay for the rising air-conditioning bills, don’t worry. Things are about to change.

The future will have to be about buildings that are naturally ventilated for as much of the year and the day as possible, for many excellent reasons, including energy costs, carbon emissions, and the basic health and safety of occupants.

Windows must be a lifesaving feature of safer, better buildings in a less predictable future–never more so than during a pandemic when the power grid fails.

Susan Roaf is an emeritus professor of architectural engineering at Heriot-Watt University.

https://www.fastcompany.com/90538499/a-disturbing-reason-so-few-buildings-have-windows-that-open

Population immunity is slowing down the pandemic in parts of the US

The large number of people already infected with the coronavirus in the US has begun to act as a brake on the spread of the disease in hard-hit states.

Millions of US residents have been infected by the virus that causes covid-19, and at least 160,000 are dead. One effect is that the pool of susceptible individuals has been depleted in many areas. After infection, it’s believed, people become immune (at least for months), so they don’t transmit the virus to others. This slows the pandemic down.

“I believe the substantial epidemics in Arizona, Florida and Texas will leave enough immunity to assist in keeping COVID-19 controlled,” Trevor Bedford, a pandemic analyst at the University of Washington, said on Friday, in a series of tweets. “However, this level of immunity is not compatible with a full return to societal behavior as existed before the pandemic.”

The exact extent to which acquired immunity is slowing the rate of transmission is unknown, but major questions like school reopening and air travel may eventually hinge on the answer.

What is known is that after rising at an alarming pace starting in May, new cases of covid-19 in Sun Belt states like Florida have started to fall. Some of that may be due to social distancing behavior, but rising rates of immunity are also a factor, according to Youyang Gu, a computer scientist whose Covid-19 Projections is among 34 pandemic models tracked by the US Centers for Disease Control and Prevention.

“Immunity may play a significant part in the regions that are declining,” says Gu. At least until the fall, which is how far his models look forward, he says, “I don’t think there is going to be another spike” of infections in southern states.  

Herd immunity

The US has been recording more than 1,000 covid-19 deaths and 45,000 confirmed cases a day. The flip side of the rapid spread, however, is there are progressively fewer vulnerable people to catch and spread the virus again. Researchers say they hope to determine how great a role the rise of this population immunity can play in managing the pandemic.

“Clearly, as susceptibility drops, disease spreading drops. No one can say different,” says Tom Britton, a statistician who models the pandemic at the University of Stockholm. “The question is to what degree is the effect because of interventions or because of immunity? In regions with very large outbreaks—New York, Milan, Madrid, and London—I am convinced it’s a combination.”

A virus outbreak will cease to grow, even without any control measures, when a threshold called herd immunity is achieved. That’s when so many people are immune that the virus can’t find new hosts quickly enough.

For the new coronavirus, the threshold for reaching herd immunity is unknown. Estimates vary widely: anywhere from 10% to 80% of the population might have to be infected, depending on how well the virus spreads but also on social factors like how much people ordinarily mix with one another.

Once an obscure inflection point known only to epidemiologists, herd immunity has gained what Francois Balloux, a systems biologist at University College London, calls “Kardashian-like” fame and become a lightning rod in politically polarized debates over economic reopening. On social media, some commenters insist that herd immunity has already arrived, meaning lockdowns and school closures are not necessary. Others find reason to doubt that immunity will ever accumulate without a vaccine and say counting on it can only lead to millions of deaths.

“It seems there is the ‘herd immunity is already reached’ team and the ‘we are all going to die’ team. The good thing is, that there is a third ‘let’s get the data and let’s look at what this all means team’ out there,” tweeted Florian Krammer, an immunologist at the Icahn School of Medicine in New York City.

What is certain is that in the US, with a raging epidemic, natural immunity is building fast. During June and July, Gu estimates, 450,000 people a day were being infected by the coronavirus in the US, the highest figures since the disease arrived in February.

That number is higher than the official case count because it includes an estimate of infections that go unseen, unfelt, or unreported. In June, CDC director Robert Redfield told reporters that the real number of infections could be many times the official tally. For instance, Gu has estimated that about 35 million Americans have now been infected—roughly 10% of the nation’s population.  

Natural infection also turns out to be extremely efficient at reducing virus transmission—even more effective than an equal number of people getting a vaccine. The reason is that the virus has been finding and infecting precisely those people who—whether because of behavior, circumstances, or biology—are most likely to be part of transmission chains.

Perhaps they are college students on spring break, or hospital nurses, or people who touch their face all the time. Whatever the reason, once these individuals become infected and are removed from the equation through death or immunity, the effect on the pandemic is outsized. By contrast, vaccinating a sheltered older person might protect that individual but does relatively less to stop transmission.

“When the disease itself causes herd immunity, it does so more efficiently than when we give out vaccine at random,” Marc Lipsitch, a public health modeler at Harvard University, told the political pundit Bill Kristol last week during a podcast interview. As a result, “there is discussion” about whether viral transmission could be reduced more quickly than generally believed, he says.

Lessons from Sweden

Outside the US, researchers are also closely tracking the role of population immunity in national responses. Sweden, for example, did not impose a strict lockdown, and saw a large number of deaths starting in April. Since then, however, the number of new infections has declined. The nation’s leaders said last week that children would go back to school unmasked.

“I would say in Sweden there is no doubt that immunity plays an important role, more than in other countries,” says Britton. “Now this epidemic is slowly stopping.”

Britton says a better understanding of how population immunity is shaping outbreaks could help guide the level and intensity of social interventions. He says the goal is to keep the virus’s reproduction number, called R, below 1, meaning every person with the virus infects fewer than one other. Under those conditions, an outbreak dwindles.

“Herd immunity is when all restrictions can be relaxed and you are still below 1,” he says. “But immunity doesn’t have to be at that level to have an effect.”

In some cities, like New York and Miami, blood tests show that 20% or more of the population has had the virus. But in regions still little affected, like small towns or rural areas, the population remains more susceptible. That means the virus can and will continue to cause new outbreaks. For instance, Louisiana saw a large spike in infections, followed by a lull and then a second spike. This occurred as the virus first hit New Orleans and later reached the rest of the state.

The geographic unevenness of the pandemic is one reason Britton does not think Sweden is able to get back to normal yet. “Are we protected from big outbreaks if all the restrictions are released? The answer is no,” he says. “On a national scale the immunity is not that high—it might be 20%. But in Stockholm it’s maybe 30 or 40%. We may be close to herd immunity [there], so they could relax restrictions a bit more.”

https://www.technologyreview.com/2020/08/11/1006366/immunity-slowing-down-coronavirus-parts-us/