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Posted on by Dr. Francis Collins
This striking portrait features the spike protein that crowns SARS-CoV-2, the coronavirus that causes COVID-19. This highly flexible protein has settled here into one of its many possible conformations during the process of docking onto a human cell before infecting it.
This portrait, however, isn’t painted on canvas. It was created on a computer screen from sophisticated 3D simulations of the spike protein in action. The aim was to map its many shape-shifting maneuvers accurately at the atomic level in hopes of detecting exploitable structural vulnerabilities to thwart the virus.
For example, notice the many chain-like structures (green) that adorn the protein’s surface (white). They are sugar molecules called glycans that are thought to shield the spike protein by sweeping away antibodies. Also notice areas (purple) that the simulation identified as the most-attractive targets for antibodies, based on their apparent lack of protection by those glycans.
This work, published recently in the journal PLoS Computational Biology , was performed by a German research team that included Mateusz Sikora, Max Planck Institute of Biophysics, Frankfurt. The researchers used a computer application called molecular dynamics (MD) simulation to power up and model the conformational changes in the spike protein on a time scale of a few microseconds. (A microsecond is 0.000001 second.)
The new simulations suggest that glycans act as a dynamic shield on the spike protein. They liken them to windshield wipers on a car. Rather than being fixed in space, those glycans sweep back and forth to protect more of the protein surface than initially meets the eye.
But just as wipers miss spots on a windshield that lie beyond their tips, glycans also miss spots of the protein just beyond their reach. It’s those spots that the researchers suggest might be prime targets on the spike protein that are especially promising for the design of future vaccines and therapeutic antibodies.
This same approach can now be applied to identifying weak spots in the coronavirus’s armor. It also may help researchers understand more fully the implications of newly emerging SARS-CoV-2 variants. The hope is that by capturing this devastating virus and its most critical proteins in action, we can continue to develop and improve upon vaccines and therapeutics.
 Computational epitope map of SARS-CoV-2 spike protein. Sikora M, von Bülow S, Blanc FEC, Gecht M, Covino R, Hummer G. PLoS Comput Biol. 2021 Apr 1;17(4):e1008790.
COVID-19 Research (NIH)
Mateusz Sikora (Max Planck Institute of Biophysics, Frankfurt, Germany)
The surprising properties of the coronavirus envelope (Interview with Mateusz Sikora), Scilog, November 16, 2020.
Posted on by Dr. Francis Collins
You may have heard about the new variants of SARS-CoV-2—the coronavirus that causes COVID-19—that have appeared in other parts of the world and have now been detected in the United States. These variants, particularly one called B.1.351 that was first identified in South Africa, have raised growing concerns about the extent to which their mutations might help them evade current antibody treatments and highly effective vaccines.
While researchers take a closer look, it’s already possible in the laboratory to predict which mutations will help SARS-CoV-2 evade our therapies and vaccines, and even to prepare for the emergence of new mutations before they occur. In fact, an NIH-funded study, which originally appeared as a bioRxiv pre-print in November and was recently peer-reviewed and published in Science, has done exactly that. In the study, researchers mapped all possible mutations that would allow SARS-CoV-2 to resist treatment with three different monoclonal antibodies developed for treatment of COVID-19 .
The work, led by Jesse Bloom, Allison Greaney, and Tyler Starr, Fred Hutchinson Cancer Center, Seattle, focused on the receptor binding domain (RBD), a key region of the spike protein that studs SARS-CoV-2’s outer surface. The virus uses RBD to anchor itself to the ACE2 receptor of human cells before infecting them. That makes the RBD a prime target for the antibodies that our bodies generate to defend against the virus.
In the new study, researchers used a method called deep mutational scanning to find out which mutations positively or negatively influence the RBD from being able to bind to ACE2 and/or thwart antibodies from striking their target. Here’s how it works: Rather than waiting for new mutations to arise, the researchers created a library of RBD fragments, each of which contained a change in a single nucleotide “letter” that would alter the spike protein’s shape and/or function by swapping one amino acid for another. It turns out that there are more than 3,800 such possible mutations, and Bloom’s team managed to make all but a handful of those versions of the RBD fragment.
The team then used a standard laboratory approach to measure systematically how each of those single-letter typos altered RBD’s ability to bind ACE2 and infect human cells. They also measured how those changes affected three different therapeutic antibodies from recognizing and binding to the viral RBD. Those antibodies include two developed by Regeneron (REGN10933 and REGN10987), which have been granted emergency use authorization for treatment of COVID-19 together as a cocktail called REGN-COV2. They also looked at an antibody developed by Eli Lilly (LY-CoV016), which is now in phase 3 clinical trials for treating COVID-19.
Based on the data, the researchers created four mutational maps for SARS-CoV-2 to escape each of the three therapeutic antibodies, as well as for the REGN-COV2 cocktail. Their studies show most of the mutations that would allow SARS-CoV-2 to escape treatment differed between the two Regeneron antibodies. That’s encouraging because it indicates that the virus likely needs more than one mutation to become resistant to the REGN-COV2 cocktail. However, it appears there’s one spot where a single mutation could allow the virus to resist REGN-COV2 treatment.
The escape map for LY-CoV016 similarly showed a number of mutations that could allow the virus to escape. Importantly, while some of those changes might impair the virus’s ability to cause infection, most of them appeared to come at little to no cost to the virus to reproduce.
How do these laboratory data relate to the real world? To begin to explore this question, the researchers teamed up with Jonathan Li, Brigham and Women’s Hospital, Boston. They looked at an immunocompromised patient who’d had COVID-19 for an unusually long time and who was treated with the Regeneron cocktail for 145 days, giving the virus time to replicate and acquire new mutations.
Viral genome data from the infected patient showed that these maps can indeed be used to predict likely paths of viral evolution. Over the course of the antibody treatment, SARS-CoV-2 showed changes in the frequency of five mutations that would change the makeup of the spike protein and its RBD. Based on the newly drawn escape maps, three of those five are expected to reduce the efficacy of REGN10933. One of the others is expected to limit binding by the other antibody, REGN10987.
The researchers also looked to data from all known circulating SARS-CoV-2 variants as of Jan. 11, 2021, for evidence of escape mutations. They found that a substantial number of mutations with potential to allow escape from antibody treatment already are present, particularly in parts of Europe and South Africa.
However, it’s important to note that these maps reflect just three important antibody treatments. Bloom says they’ll continue to produce maps for other promising therapeutic antibodies. They’ll also continue to explore where changes in the virus could allow for escape from the more diverse set of antibodies produced by our immune system after a COVID-19 infection or vaccination.
While it’s possible some COVID-19 vaccines may offer less protection against some of these new variants—and recent results have suggested the AstraZeneca vaccine may not provide much protection against the South African variant, there’s still enough protection in most other current vaccines to prevent serious illness, hospitalization, and death. And the best way to keep SARS-CoV-2 from finding new ways to escape our ongoing efforts to end this terrible pandemic is to double down on whatever we can do to prevent the virus from multiplying and spreading in the first place.
For now, emergence of these new variants should encourage all of us to take steps to slow the spread of SARS-CoV-2. That means following the three W’s: Wear a mask, Watch your distance, Wash your hands often. It also means rolling up our sleeves to get vaccinated as soon as the opportunity arises.
 Prospective mapping of viral mutations that escape antibodies used to treat COVID-19.
Starr TN, Greaney AJ, Addetia A, Hannon WW, Choudhary MC, Dingens AS, Li JZ, Bloom JD.
Science. 2021 Jan 25:eabf9302.
COVID-19 Research (NIH)
Bloom Lab (Fred Hutchinson Cancer Center, Seattle)
NIH Support: National Institute of Allergy and Infectious Diseases
Posted on by Dr. Francis Collins
It usually takes more than a decade to develop a safe, effective anti-viral therapy. But, when it comes to coronavirus disease 2019 (COVID-19), we don’t have that kind of time. One way to speed the process may be to put some old drugs to work against this new disease threat. This is generally referred to as “drug repurposing.”
NIH has been doing everything possible to encourage screens of existing drugs that have been shown safe for human use. In a recent NIH-funded study in the journal Nature, researchers screened a chemical “library” that contained nearly 12,000 existing drug compounds for their potential activity against SARS-CoV-2, the novel coronavirus that causes COVID-19 . The results? In tests in both non-human primate and human cell lines grown in laboratory conditions, 21 of these existing drugs showed potential for repurposing to thwart the novel coronavirus—13 of them at doses that likely could be safely given to people. The majority of these drugs have been tested in clinical trials for use in HIV, autoimmune diseases, osteoporosis, and other conditions.
These latest findings come from an international team led by Sumit Chanda, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA. The researchers took advantage of a small-molecule drug library called ReFRAME , which was created in 2018 by Calibr, a non-profit drug discovery division of Scripps Research, La Jolla, CA.
In collaboration with Yuen Kwok-Yung’s team at the University of Hong Kong, the researchers first developed a high-throughput method that enabled them to screen rapidly each of the 11,987 drug compounds in the ReFRAME library for their potential to block SARS-CoV-2 in cells grown in the lab. The first round of testing narrowed the list of possible COVID-19 drugs to about 300. Next, using lower concentrations of the drugs in cells exposed to a second strain of SARS-CoV-2, they further narrowed the list to 100 compounds that could reliably limit growth of the coronavirus by at least 40 percent.
Generally speaking, an effective anti-viral drug is expected to show greater activity as its concentration is increased. So, Chanda’s team then tested those 100 drugs for evidence of such a dose-response relationship. Twenty-one of them passed this test. This group included remdesivir, a drug originally developed for Ebola virus disease and recently authorized by the U.S. Food and Drug Administration (FDA) for emergency use in the treatment of COVID-19. Remdesivir could now be considered a positive control.
These findings raised another intriguing question: Could any of the other drugs with a dose-response relationship work well in combination with remdesivir to block SARS-CoV-2 infection? Indeed, the researchers found that four of them could.
Further study showed that some of the most promising drugs on the list reduced the number of SARS-CoV-2 infected cells by 65 to 85 percent. The most potent of these was apilimod, a drug that has been evaluated in clinical trials for treating Crohn’s disease, rheumatoid arthritis, and other autoimmune conditions. Apilimod is now being evaluated in the clinic for its ability to prevent the progression of COVID-19. Another potential antiviral to emerge from the study is clofazimine, a 70-year old FDA-approved drug that is on the World Health Organization’s list of essential medicines for the treatment of leprosy.
Overall, the findings suggest that there may be quite a few existing drugs and/or experimental drugs fairly far along in the development pipeline that have potential to be repurposed for treating COVID-19. What’s more, some of them might also work well in combination with remdesivir, or perhaps other drugs, as treatment “cocktails,” such as those used to successfully treat HIV and hepatitis C.
This is just one of a wide variety of drug screening efforts that are underway, using different libraries and different assays to detect activity against SARS-CoV-2. The NIH’s National Center for Advancing Translational Sciences has established an open data portal to collect all of these data as quickly and openly as possible. As NIH continues its efforts to use the power of science to end the COVID-19 pandemic, it is critically important that we explore as many avenues as possible for developing diagnostics, treatments, and vaccines.
 Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Riva L, Yuan S, Yin X, et al. Nature. 2020 Jul 24 [published online ahead of print]
 The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Janes J, Young ME, Chen E, et al. Proc Natl Acad Sci USA. 2018;115(42):10750-10755.
Coronavirus (COVID-19) (NIH)
ReFRAMEdb (Scripps Research, La Jolla, CA)
The Chanda Lab (Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA)
Yuen Kwok-Yung (University of Hong Kong)
OpenData|Covid-19 (National Center for Advancing Translational Sciences/NIH)
NIH Support: National Institute of Allergy and Infectious Diseases; National Institute of General Medical Sciences
Posted on by Dr. Francis Collins
Drug overdoses continue to take far too many lives, driven primarily by the opioid crisis (though other drugs, such as methamphetamine and cocaine, are also major concerns). While NIH’s Helping to End Addiction Long-term (HEAL) Initiative is taking steps to address this terrible crisis, new findings serve as another wake-up call that young people battling opioid addiction need a lot more assistance to get back on the right track.
In a study of more than 3,600 individuals, aged 13-22, who survived an opioid overdose, an NIH-funded team found that only about one-third received any kind of follow-up addiction treatment . Even more troubling, less than 2 percent of these young people received the gold standard approach of medication treatment.
The findings reported in JAMA Pediatrics come from Rachel Alinsky, an adolescent medicine and addiction medicine fellow at Johns Hopkins Children’s Center, Baltimore. She saw first-hand the devastating toll that opioids are taking on our youth.
Alinsky also knew that nationally more than 4,000 fatal opioid overdoses occurred in people between the ages of 15 and 24 in 2016 . Likewise, rates of nonfatal opioid overdoses for teens and young adults also have been escalating, leading to more than 7,000 hospitalizations and about 28,000 emergency department visits in 2015 alone .
In the latest study, Alinsky wanted to find out whether young people who overdose receive timely treatment to help prevent another life-threatening emergency. According to our best evidence-based guidelines, timely treatment for youth with an opioid addiction should include medication, ideally along with behavioral interventions.
That’s because opioid addiction rewires the brain—will power alone is simply not sufficient to achieve and sustain recovery. After one overdose, the risk of dying from another one rises dramatically. So, it is critical to get those who survived an overdose into effective treatment right away.
Alinsky and her team dove into the best-available dataset, consisting of data on more than 4 million mostly low-income adolescents and young adults who’d been enrolled in Medicaid for at least six months in 16 states. The sample included 3,606 individuals who’d been seen by a doctor and diagnosed with opioid poisoning. A little over half of them were female; most were non-Hispanic whites.
Heroin accounted for about a quarter of those overdoses. The rest involved other opioids, most often prescription painkillers. However, the researchers note that some overdoses attributed to heroin might have been caused by the powerful synthetic opioid fentanyl. The use of fentanyl, often mixed with heroin, was on the rise in the study’s final years, but it was rarely included in drug tests at the time.
Less than 20 percent of young people in the sample received a diagnosis of opioid use disorder, or a problematic pattern of opioid use resulting in impairment or distress. What’s more, in the month following an overdose, few received the current standard for addiction treatment, which should include behavioral therapy and treatment with one of three drugs: buprenorphine, naltrexone, or methadone.
Drilling a little deeper into the study’s findings:
• 68.9 percent did not receive addiction treatment of any kind.
• 29.3 percent received behavioral health services alone.
• Only 1.9 percent received one of three approved medications for opioid use disorder.
It’s been estimated previously that teens and young adults are one-tenth as likely as adults 25 years and older to get the recommended treatment for opioid use disorder . How can that be? The researchers suggest that one factor might be inexperience among pediatricians in diagnosing and treating opioid addiction. They also note that, even when the problem is recognized, doctors sometimes struggle to take the next step and connect young people with addiction treatment facilities that are equipped to provide the needed treatment to adolescents.
As this new study shows, interventions designed to link teens and young adults with the needed recovery treatment and care are desperately needed. As we continue to move forward in tackling this terrible crisis through the NIH’s HEAL Initiative and other efforts, finding ways to overcome such systemic barriers and best engage our youth in treatment, including medication, will be essential.
 Receipt of addiction treatment after opioid overdose among Medicaid-enrolled adolescents and young adults. Alinsky RH, Zima BT, Rodean J, Matson PA, Larochelle MR, Adger H Jr, Bagley SM, Hadland SE. JAMA Pediatr. 2020 Jan 6:e195183.
 Overdose death rates. National Institute on Drug Abuse, NIH.
 2018 annual surveillance drug-related risks and outcomes—United States: surveillance special report. Centers for Disease Control and Prevention.
 Medication-assisted treatment for adolescents in specialty treatment for opioid use disorder. Feder KA, Krawczyk N, Saloner B. J Adolesc Health. 2017 Jun;60(6):747-750.
Opioid Overdose Crisis (National Institute on Drug Abuse/NIH)
Opioid Overdose (Centers for Disease Control and Prevention, Atlanta)
Decisions in Recovery: Treatment for Opioid Use Disorder (Substance Abuse and Mental Health Services Administration, Rockville, MD)
Rachel Alinsky (Johns Hopkins University Children’s Center, Baltimore)
NIH Support: Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse