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Rensselaer researchers receive $3.5 million grant for development of COVID antiviral drug

TROY, N.Y. —  Rensselaer Polytechnic Institute researchers Gaetano Montelione and Christopher Cioffi will use a five-year, $3.5 million grant from the…

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TROY, N.Y. —  Rensselaer Polytechnic Institute researchers Gaetano Montelione and Christopher Cioffi will use a five-year, $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to develop a low-dose, oral COVID antiviral drug that can be administered at home. Dr. Montelione is the Constellation Endowed Chair of Structural Bioinformatics and Dr. Cioffi is the Thomas and Constance D’Ambra Endowed Chair of Organic Chemistry. Both are professors in the Department of Chemistry and Chemical Biology.

Credit: RPI

TROY, N.Y. —  Rensselaer Polytechnic Institute researchers Gaetano Montelione and Christopher Cioffi will use a five-year, $3.5 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), to develop a low-dose, oral COVID antiviral drug that can be administered at home. Dr. Montelione is the Constellation Endowed Chair of Structural Bioinformatics and Dr. Cioffi is the Thomas and Constance D’Ambra Endowed Chair of Organic Chemistry. Both are professors in the Department of Chemistry and Chemical Biology.

Rensselaer’s research is part of the consortium of a new antiviral drug development center, called the Center for Antiviral Medicines and Pandemic Preparedness (CAMPP), that will be led by Scripps Research. The center will be one of nine NIAID-sponsored Antiviral Drug Discovery (AViDD) Centers for Pathogens of Pandemic Concern.

“Our role in the project is to develop novel inhibitors of the two key proteases of the SARS-CoV-2 virus, called CLpro and PLpro, which are essential to the virus life cycle,” Dr. Montelione said.

The Rensselaer team will collaborate with Drs. Sumit Chanda and Arnab Chatterjee of Scripps Research Institute, Dr. Adolfo Garcia-Sastre of the Mount Sinai School of Medicine, and Dr. Stefano Ciurli of the University of Bologna, Italy.

The team’s work will build upon Dr. Montelione’s previous research. First, using bioinformatics, Dr. Montelione and his team found that a key protein from the hepatitis C virus closely resembles the coronavirus CLpro protease structure. Since several Food and Drug Administration (FDA)-approved drugs target the hepatitis C protease, the next step was to determine if any of those drugs would also bind and block proteases of SARS-CoV-2.

In research published in Cell Reports, the team found that, out of the 10 hepatitis C drugs tested, seven suppressed the SARS-CoV-2 virus. Three of those drugs were acting not only on the main protease, CLpro, but on the PLpro protease, as well. Next, they discovered that, when combined with the polymerase inhibitor remdesivir, these drugs multiplied remdesivir’s antiviral activity by as much as tenfold. Those that only inhibit CLpro did not amplify remdesivir’s effect.

“Inhibiting PLpro seems to be important,” Dr. Cioffi said. “This induces synergy with other antivirals such as remdesivir, which is currently being used to treat people with COVID-19. Now, we will work toward making new and orally bioavailable PLpro inhibitors based on Dr. Montelione’s biophysical analysis. We will look at the structure of the protein’s active site and design molecules that fit into it and bind with optimal affinity.”

CLpro will also be targeted.

“One of the big challenges is that the target will evolve to escape the drug,” Dr. Montelione said. “This is particularly problematic with rapidly mutating viruses like COVID-19. To overcome that, we try to hit multiple targets. By hitting both CLpro and PLpro simultaneously, there is less likelihood of antiviral resistance.”

“Rensselaer is fortunate to have two distinguished faculty members working together on complementary aspects of a new COVID-19 therapy,” said Dr. Curt Breneman, Dean of the School of Science. “Through their innovative strategy of designing tandem protease inhibitors, new and highly effective COVID-19 treatments are now on the horizon.”

It is hoped that the most promising antiviral drug candidates to come out of the AViDD centers will enter late-stage preclinical development. Industry partners will provide valuable resources to accelerate their movement through the product development pipeline. Drugs that are already FDA-approved for treating different diseases may be approved quicker for the treatment of COVID-19, as well.

The Rensselaer research team will include Thomas Acton, Khushboo Bafna, Namita Dube, Rebecca Green-Cramer, Arunan Palanimuthu, and Theresa Ramelot. 

 

About Rensselaer Polytechnic Institute

Founded in 1824, Rensselaer Polytechnic Institute is America’s first technological research university. Rensselaer encompasses five schools, over 30 research centers, more than 140 academic programs including 25 new programs, and a dynamic community made up of over 6,800 students and 104,000 living alumni. Rensselaer faculty and alumni include upwards of 155 National Academy members, six members of the National Inventors Hall of Fame, six National Medal of Technology winners, five National Medal of Science winners, and a Nobel Prize winner in Physics. With nearly 200 years of experience advancing scientific and technological knowledge, Rensselaer remains focused on addressing global challenges with a spirit of ingenuity and collaboration. To learn more, please visit www.rpi.edu.

 

Contact: 

Katie Malatino

Sr. Communications Specialist

518-276-2146

 

Deanna Cohen

Director of Media Relations

518-233-4828

cohend8@rpi.edu

 

For general inquiries: newsmedia@rpi.edu

 

Visit the Rensselaer research and discovery blog: https://everydaymatters.rpi.edu/

 

Follow us on Twitter: @RPINews

 


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Spread & Containment

Pfizer bid for sickle cell drug developer GBT said to be imminent

Pfizer is on the brink of announcing a deal to buy Global Blood Therapeutics (GBT) and its oral
The post Pfizer bid for sickle cell drug developer GBT…

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Pfizer is on the brink of announcing a deal to buy Global Blood Therapeutics (GBT) and its oral therapy Oxbryta for sickle cell disease for around $5 billion, according to press reports.

A deal could be announced as early as today, when GBT is scheduled to report its second quarter results, according to a Wall Street Journal report citing people familiar with the matter. Neither GBT nor Pfizer has commented on the rumour.

If confirmed, it will be another example of Pfizer leveraging the windfall cash generated by its COVID-19 vaccine Comirnaty and oral antiviral therapy Paxlovid to beef up its pipeline of new therapies, coming a few months after it closed a $6.7 billion acquisition of Arena Pharma and made an $11.6 billion takeover bid for Biohaven.

GBT won FDA approval for Oxbryta (voxelotor) as a daily tablet for the treatment of SCD in patients aged 12 and over in 2019, extending its use to include younger children aged four and over last December, and earlier this year also got a green light from regulators in Europe for the over 12s.

The $125,000-a-year drug is a haemoglobin polymerisation inhibitor designed to prevent the deformation or ‘sickling’ of red blood cells associated with the disease, and has been tipped to become a $1 billion-plus product.

Sales of Oxbryta have been a little slow to gather momentum, mainly because of payer resistance in the US, but are picking up the pace with a 41% rise to $55 million in the first quarter of this year.

There are around 100,000 people in the US living with SCD, and more than 20 million globally, according to the FDA.

If a deal is forthcoming, Pfizer would also claim inclacumab, a P-selectin inhibitor in phase 3 testing for prevention of the painful vaso-occlusive crises that afflict people living with SCD , as well as an early-stage polymerisation inhibitor called GBT021601 intended as a follow-up to Oxbryta.

Other suitors are also reported to be circling GBT however, according to Bloomberg, whose report sparked a 33% spike in GBT shares to more than $68 on Friday, not far shy of the company’s 52-week high of $73 and giving it a market capitalisation of more than $4 billion.

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Here We Go Again – Monkeypox Communications Challenges

In February 2020 I published a blog posting – Emerging Pathogens, Communications – that encapsulated my observations and learnings from my years work…

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Source: CDC

In February 2020 I published a blog posting – Emerging Pathogens, Communications – that encapsulated my observations and learnings from my years work in the early years of the HIV/AIDS pandemic in the early 1980s. As we sit, possibly, on the cusp of another large scale medical challenge with monkeypox, it seemed like a good idea to revisit the topic. When there is a new and scary thing we are facing, medically speaking, there are some truisms regarding the communications environment that can inform strategic thinking about how we talk about it.

  1. Facts are low, speculation is high – And nature hates a vacuum and there will be many who are willing to fill the void with misinformation. People want facts, and the fact is, facts are in short supply.
  2. Numbers don’t mean a lot – First of all, they change quickly – and are changing very quickly with monkeypox. In addition, there is often a lack of accurate reporting for many reasons.
  3. Points of reference will change – What we know, and what we don’t know, will change over time as we get more experience and gain wider understanding. That might seem like a good thing, but in fact, changing stories undermine credibility.
  4. Fraud potential is high – There are people who will take advantage of the situation and exploit it for political and/or financial gain. That, too, impacts credibility and can confuse people.
  5. Policy is likely to be ham-handed – Policies may be developed quickly and without adequate information and be based on emotion and bias more than facts. This is another factor that strains credibility.

Monkeypox is not COVID, and COVID was not AIDS. They each present distinct challenges and evoke particular fears and concerns. There are big differences between the three. But they are all viruses. And when it comes to communications challenges there are many commonalities.

First and foremost, in the absence of facts, fear can drive actions. And when a pathogen is newly emerging, facts are greatly outnumbered by questions. The degree to which companies, educators, businesses and service providers may want to prepare to deal with those challenges may depend on where they are, who their stakeholders are, and how big or small they are. At this stage though, better to consider the challenges that may lay before you know, before they present themselves.

Source: CDC

Analysis

It may be that monkeypox is contained early if we are lucky. There are reported signs that transmission may be slowing in the U.K. and the trend in the graph above appears to show some deceleration. That said, the numbers have increased quickly on an extremely steep curve. That means there is an increasing amount of virus out there. The virus has mainly spread among men who have sex with men and transmission is being attributed to skin contact. But the higher the numbers go the greater potential there is for more lateral spread. A presumptive pediatric case was reported last week in California. It is also a virus that can move between people and animals.

Containment depends on systems that are able to screen, test, treat, and prevent (both by means of avoiding circumstances that can enhance transmission and by vaccination). To that end, many things are not in our favor. An extremely splintered approach at federal, state and local levels impacts the coordination of a public health response. We have COVID fatigue in the extreme. And in terms of tools, we do not have a means for screening, meaning we do not know who is infected before they exhibit symptoms which may take several days; the testing situation is complicated because there is no quick, at-home testing like there is for COVID and may be best applied when there are lesions. But people may have other symptoms such as headache, chills, muscle aches, swollen lymph nodes and exhaustion. The only FDA-approved drug to treat is approved for smallpox, but no Monkeypox and has been difficult to access. In terms of prevention, while a vaccine has been developed, supply is very short and it, too, has been hard to get.

Additional challenges include the fact that the course of illness runs two to four weeks. If a person must self-isolate for that length of time it is not only difficult, but there may be unintended consequences. With men who have sex with men comprising the overwhelming majority of cases, a diagnosis is the equivalent of coming out. For many gay men that is not a problem. For many others, who may have wives and children, it can be a very large one, facing a situation that may have both personal and professional peril.

At the present time, there are some states which are reporting higher numbers than others. If the numbers do continue to climb, then a larger number of geographies will be impacted and most likely a wider circle of people, raising the chances that large employers, those in specific sectors, may face communications challenges sooner rather than later such as:

  • Travel and hospitality
  • Schools and universities
  • Hospitals
  • Institutional settings such as daycare centers, rehab and nursing homes (a case of a daycare workers was reported in Illinois last week)

What to Do

Every business, service or place of public accommodation is different. There is no one-size-fits-all approach to preparation. One must consider the size of the enterprise, the stakeholders and the level of physical contact and interaction with surfaces. That said, there are echos from both AIDS and COVID that shed light into how people may react to the emergence of another communicable condition. A few things to consider:

  • Review policies and assess what may need to be changed or amended; this is not just COVID return-to-work policies, but discrimination policies as well. Re-think many of the things you have had to communicate about a virus transmitted by air, and re-fashion to think about surfaces. Monkeypox will present distinct challenges.
  • Consider the questions and issues you may face. Can we catch monkeypox using the toilet? Trying on clothes? Do I have to sit next to the gay man? My co-worker says it is eczema, I’m afraid it is Monkeypox. Depending on your business, your clientele, there are different sets of questions that may arise for different settings. Think about what they might be and to what degree you are the one to have to provide the answers.
  • Assess the triggers for potential fear and conflict between employees, customers and users of any service.
  • Communicating in an environment where what we know changes, and what was certain yesterday may be uncertain tomorrow is always a strain on credibility. Therefore consider integrating reminders to that effect in your communications. What we know now is….
  • Gather reliable resources – the obvious ones such as CDC, FDA, and Departments of Health at the state and local levels, but also consider credible grassroots organizations, particularly ones that may resonate with stakeholders, particularly those dealing with gay-related health issues and key medical societies such as the American Society for Microbiology and others.

Many people think that preparation during such a nascent phase of the outbreak is over-reacting. I hope they are right. But having lived through AIDS and COVID, and seen early numbers quickly spell a different story over a very short period of time, one may be well-served to think it through now.

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Fatigue, headache among top lingering symptoms months after COVID

AUGUSTA, Ga. (Aug. 8, 2022) – Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from…

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AUGUSTA, Ga. (Aug. 8, 2022) – Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from having COVID-19, investigators report.

Credit: Augusta University

AUGUSTA, Ga. (Aug. 8, 2022) – Fatigue and headache were the most common symptoms reported by individuals an average of more than four months out from having COVID-19, investigators report.

Muscle aches, cough, changes in smell and taste, fever, chills and nasal congestion were next in the long line of lingering symptoms.

“Our results support the growing evidence that there are chronic neuropsychiatric symptoms following COVID-19 infections,” Medical College of Georgia investigators write in the journal ScienceDirect

“There are a lot of symptoms that we did not know early on in the pandemic what to make of them, but now it’s clear there is a long COVID syndrome and that a lot of people are affected,” says Dr. Elizabeth Rutkowski, MCG neurologist and the study’s corresponding author.

The published study reports on preliminary findings from the first visit of the first 200 patients enrolled in the COVID-19 Neurological and Molecular Prospective Cohort Study in Georgia, or CONGA, who were recruited on average about 125 days after testing positive for the COVID-19 virus.

CONGA was established at MCG early in the pandemic in 2020 to examine the severity and longevity of neurological problems and began enrolling participants in March 2020 with the ultimate goal of recruiting 500 over five years.

Eighty percent of the first 200 participants reported neurological symptoms with fatigue, the most common symptom, reported by 68.5%, and headache close behind at 66.5%. Just over half reported changes in smell (54.5%) and taste (54%) and nearly half the participants (47%) met the criteria for mild cognitive impairment, with 30% demonstrating impaired vocabulary and 32% having impaired working memory.

Twenty-one percent reported confusion, and hypertension was the most common medical condition reported by participants in addition to their bout with COVID-19.

No participants reported having a stroke, weakness or inability to control muscles involved with speaking, and coordination problems were some of the less frequently reported symptoms.

Twenty-five percent met the criteria for depression, and diabetes, obesity, sleep apnea and a history of depression were associated with those who met the criteria. Anemia and a history of depression were associated with the 18% who met the objective criteria for anxiety.

While the findings to date are not surprising and are consistent with what other investigators are finding, Rutkowski says the fact that symptoms reported by participants often didn’t match what objective testing indicated, was surprising. And, it was bidirectional.

For example, the majority of participants reported taste and smell changes, but objective testing of both these senses did not always line up with what they reported. In fact, a higher percentage of those who did not report the changes actually had evidence of impaired function based on objective measures, the investigators write. While the reasons are not certain, part of the discrepancy may be a change in the quality of their taste and smell rather than pure impaired ability, Rutkowski says.

“They eat a chicken sandwich and it tastes like smoke or candles or some weird other thing but our taste strips are trying to depict specific tastes like salty and sweet,” Rutkowski says. Others, for example, may rely on these senses more, even when they are preparing the food, and may be apt to notice even a slight change, she says.

Either way, their data and others suggest a persistent loss of taste and smell following COVID-19, Rutkowski and her colleagues write.

Many earlier reports have been based on these kinds of self-reports, and the discrepancies they are finding indicate that approach may not reflect objective dysfunction, the investigators write.

On the other hand, cognitive testing may overestimate impairment in disadvantaged populations, they report.

The first enrollees were largely female, 35.5% were male. They were an average of 44.6 years old, nearly 40% were Black and 7% had been hospitalized because of COVID-19. Black participants were generally disproportionately affected, the investigators say.

Seventy-five percent of Black participants and 23.4% of white participants met criteria for mild cognitive impairment. The findings likely indicate that cognitive tests assess different ethnic groups differently. And, socioeconomic, psychosocial (issues like family problems, depression and sexual abuse) and physical health factors generally may disproportionately affect Black individuals, the investigators write. It also could mean that cognitive testing may overestimate clinical impairment in disadvantaged populations, they write.

Black and Hispanic individuals are considered twice as likely to be hospitalized by COVID-19 and ethnic and racial minorities are more likely to live in areas with higher rates of infection. Genetics also is a likely factor for their increased risk for increased impact from COVID, much like being at higher risk for hypertension and heart disease early and more severely in life.

A focus of CONGA is to try to better understand how increased risk and effects from COVID-19 impact Blacks, who comprise about 33% of the state’s population.

A reason fatigue appears to be such a major factor among those who had COVID-19 is potentially because of levels of inflammation, the body’s natural response to an infection, remain elevated in some individuals. For example, blood samples taken at the initial visit and again on follow up showed some inflammatory markers were up and stayed up in some individuals.

These findings and others indicate that even though the antibodies to the virus itself may wain, persistent inflammation is contributing to some of the symptoms like fatigue, she says. She notes patients with conditions like multiple sclerosis and rheumatoid arthritis, both considered autoimmune conditions that consequently also have high levels of inflammation, also include fatigue as a top symptom.

“They have body fatigue where they feel short of breath, they go to get the dishes done and they are feeling palpitations, they immediately have to sit down and they feel muscle soreness like they just ran a mile or more,” Rutkowski says.

“There is probably some degree of neurologic fatigue as well because patients also have brain fog, they say it hurts to think, to read even a single email and that their brain is just wiped out,” she says. Some studies have even shown shrinkage of brain volume as a result of even mild to moderate disease. 

These multisystem, ongoing concerns are why some health care facilities have established long COVID clinics where physicians with expertise in the myriad of problems they are experiencing gather to see each patient.

CONGA participants who reported more symptoms and problems tended to have depression and anxiety.

Problems like these as well as mild cognitive impairment and even impaired vocabulary may also reflect the long-term isolation COVID-19 produced for many individuals, Rutkowski says.

“You are not doing what you would normally do, like hanging out with your friends, the things that bring most people joy,” Rutkowski says. “On top of that, you may be dealing with physical ailments, lost friends and family members and loss of your job.”

For CONGA, participants self-report symptoms and answer questions about their general state of health like whether they smoked, drank alcohol, exercised, and any known preexisting medical conditions. But they also receive an extensive neurological exam that looks at fundamentals like mental status, reflexes and motor function. They also take established tests to assess cognitive function with results being age adjusted. They also do at-home extensive testing where they are asked to identify odors and the ability to taste sweet, sour, bitter, salty, brothy or no taste. They also have blood analysis done to look for indicators of lingering infection like those inflammatory markers and oxidative stress.

Neuropsychiatric symptoms are observed in the acute phase of infection, but there is a need for accurate characterization of how symptoms evolve over time, the investigators write.

And particularly for some individuals, symptoms definitely linger. Even some previously high-functioning individuals, who normally worked 80 hours a week and exercised daily, may find themselves only able to function about an hour a day and be in the bed the remainder, Rutkowski says.

The investigators are searching for answers to why and how, and while Rutkowski says she cannot yet answer all their questions, she can tell them with certainty that they are not alone or “crazy.”  

One of the best things everyone can do moving forward is to remain diligent about avoiding infection, including getting vaccinated or boosted to help protect your brain and body from long COVID symptoms and help protect others from infection, Rutkowski says. There is evidence that the more times you are infected, the higher the risk of ongoing problems.

Rutkowski notes that their study findings may be somewhat biased toward high percentages of ongoing symptoms because the study likely is attracting a high percentage of individuals with concerns about ongoing problems.

SARS-CoV-2 is thought to have first infected people in late 2019 and is a member of the larger group of coronaviruses, which have been a source of upper respiratory tract infections, like the common cold, in people for years.

At least part of the reason SARS-CoV-2 is believed to have such a wide-ranging impact is that the virus is known to attach to angiotensin-converting enzyme-2, or ACE2, which is pervasive in the body. ACE2 has a key role in functions like regulating blood pressure and inflammation. It’s found on neurons, cells lining the nose, mouth, lungs and blood vessels, as well as the heart, kidneys and gastrointestinal tract. The virus attaches directly to the ACE2 receptor on the surface of cells, which functions much like a door to let the virus inside.

Experience and study since COVID-19 started both indicate immediate neurological impact can include loss of taste and smell, brain infection, headaches and, less commonly, seizures, stroke and damage or death of nerves. As time has passed, there is increasing evidence that problems like loss of taste and smell, can become chronic, as well as problems like brain fog, extreme fatigue, depression, anxiety and insomnia, the investigators write. Persistent conditions including these and others are now referenced as “long Covid.”

The research was supported by funding from the National Institute of Neurological Disorders and Stroke and philanthropic support from the TR Reddy Family Fund.

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