But a family of meteorites has befuddled researchers since its discovery in the 1960s. The diverse fragments, found all over the world, seem to have broken off from the same primordial body, and yet the makeup of these meteorites indicates that their parent must have been a puzzling chimera that was both melted and unmelted.

Now researchers at MIT and elsewhere have determined that the parent body of these rare meteorites was indeed a multilayered, differentiated object that likely had a liquid metallic core. This core was substantial enough to generate a magnetic field that may have been as strong as Earth’s magnetic field is today.

Their results, published in the journal Science Advances, suggest that the diversity of the earliest objects in the solar system may have been more complex than scientists had assumed.

“This is one example of a planetesimal that must have had melted and unmelted layers. It encourages searches for more evidence of composite planetary structures,” says lead author Clara Maurel, a graduate student in MIT’s Department of Earth, Atmospheric, and Planetary Sciences (EAPS). “Understanding the full spectrum of structures, from nonmelted to fully melted, is key to deciphering how planetesimals formed in the early solar system.”

Maurel’s co-authors include EAPS professor Benjamin Weiss, along with collaborators at Oxford University, Cambridge University, the University of Chicago, Lawrence Berkeley National Laboratory, and the Southwest Research Institute.

Oddball irons

The solar system formed around 4.5 billion years ago as a swirl of super-hot gas and dust. As this disk gradually cooled, bits of matter collided and merged to form progressively larger bodies, such as planetesimals.

The majority of meteorites that have fallen to Earth have compositions that suggest they came from such early planetesimals that were either of two types: melted, and unmelted. Both types of objects, scientists believe, would have formed relatively quickly, in less than a few million years, early in the solar system’s evolution.

If a planetesimal formed in the first 1.5 million years of the solar system, short-lived radiogenic elements could have melted the body entirely due to the heat released by their decay. Unmelted planetesimals could have formed later, when their material had lower quantities of radiogenic elements, insufficient for melting.

There has been little evidence in the meteorite record of intermediate objects with both melted and unmelted compositions, except for a rare family of meteorites called IIE irons.

“These IIE irons are oddball meteorites,” Weiss says. “They show both evidence of being from primordial objects that never melted, and also evidence for coming from a body that’s completely or at least substantially melted. We haven’t known where to put them, and that’s what made us zero in on them.”

Magnetic pockets

Scientists have previously found that both melted and unmelted IIE meteorites originated from the same ancient planetesimal, which likely had a solid crust overlying a liquid mantle, like Earth. Maurel and her colleagues wondered whether the planetesimal also may have harbored a metallic, melted core.

“Did this object melt enough that material sank to the center and formed a metallic core like that of the Earth?” Maurel says. “That was the missing piece to the story of these meteorites.”

The team reasoned that if the planetesimal did host a metallic core, it could very well have generated a magnetic field, similar to the way Earth’s churning liquid core produces a magnetic field. Such an ancient field could have caused minerals in the planetesimal to point in the direction of the field, like a needle in a compass. Certain minerals could have kept this alignment over billions of years.

Maurel and her colleagues wondered whether they might find such minerals in samples of IIE meteorites that had crashed to Earth. They obtained two meteorites, which they analyzed for a type of iron-nickel mineral known for its exceptional magnetism-recording properties.

The team analyzed the samples using the Lawrence Berkeley National Laboratory’s Advanced Light Source, which produces X-rays that interact with mineral grains at the nanometer scale, in a way that can reveal the minerals’ magnetic direction.

Sure enough, the electrons within a number of grains were aligned in a similar direction — evidence that the parent body generated a magnetic field, possibly up to several tens of microtesla, which is about the strength of Earth’s magnetic field. After ruling out less plausible sources, the team concluded that the magnetic field was most likely produced by a liquid metallic core. To generate such a field, they estimate the core must have been at least several tens of kilometers wide.

Such complex planetesimals with mixed composition (both melted, in the form of a liquid core and mantle, and unmelted in the form of a solid crust), Maurel says, would likely have taken over several million years to form — a formation period that is longer than what scientists had assumed until recently.

But where within the parent body did the meteorites come from? If the magnetic field was generated by the parent body’s core, this would mean that the fragments that ultimately fell to Earth could not have come from the core itself. That’s because a liquid core only generates a magnetic field while still churning and hot. Any minerals that would have recorded the ancient field must have done so outside the core, before the core itself completely cooled.

Working with collaborators at the University of Chicago, the team ran high-velocity simulations of various formation scenarios for these meteorites. They showed that it was possible for a body with a liquid core to collide with another object, and for that impact to dislodge material from the core. That material would then migrate to pockets close to the surface where the meteorites originated.

“As the body cools, the meteorites in these pockets will imprint this magnetic field in their minerals. At some point, the magnetic field will decay, but the imprint will remain,” Maurel says. “Later on, this body is going to undergo a lot of other collisions until the ultimate collisions that will place these meteorites on Earth’s trajectory.”

Was such a complex planetesimal an outlier in the early solar system, or one of many such differentiated objects? The answer, Weiss says, may lie in the asteroid belt, a region populated with primordial remnants.

“Most bodies in the asteroid belt appear unmelted on their surface,” Weiss says. “If we’re eventually able to see inside asteroids, we might test this idea. Maybe some asteroids are melted inside, and bodies like this planetesimal are actually common.”

This research was funded, in part, by NASA.

Now, an international team of researchers led by neuroscientists at Harvard Medical School has identified the olfactory cell types most vulnerable to infection by SARS-CoV-2, the virus that causes COVID-19.

Surprisingly, sensory neurons that detect and transmit the sense of smell to the brain are not among the vulnerable cell types.

Reporting in Science Advances on July 24, the research team found that olfactory sensory neurons do not express the gene that encodes the ACE2 receptor protein, which SARS-CoV-2 uses to enter human cells. Instead, ACE2 is expressed in cells that provide metabolic and structural support to olfactory sensory neurons, as well as certain populations of stem cells and blood vessel cells.

The findings suggest that infection of nonneuronal cell types may be responsible for anosmia in COVID-19 patients and help inform efforts to better understand the progression of the disease.

“Our findings indicate that the novel coronavirus changes the sense of smell in patients not by directly infecting neurons but by affecting the function of supporting cells,” said senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at HMS.

This implies that in most cases, SARS-CoV-2 infection is unlikely to permanently damage olfactory neural circuits and lead to persistent anosmia, Datta added, a condition that is associated with a variety of mental and social health issues, particularly depression and anxiety.

“I think it’s good news, because once the infection clears, olfactory neurons don’t appear to need to be replaced or rebuilt from scratch,” he said. “But we need more data and a better understanding of the underlying mechanisms to confirm this conclusion.”

A majority of COVID-19 patients experience some level of anosmia, most often temporary, according to emerging data. Analyses of electronic health records indicate that COVID-19 patients are 27 times more likely to have smell loss but are only around 2.2 to 2.6 times more likely to have fever, cough or respiratory difficulty, compared to patients without COVID-19.

Some studies have hinted that anosmia in COVID-19 differs from anosmia caused by other viral infections, including by other coronaviruses.

For example, COVID-19 patients typically recover their sense of smell over the course of weeks — much faster than the months it can take to recover from anosmia caused by a subset of viral infections known to directly damage olfactory sensory neurons. In addition, many viruses cause temporary loss of smell by triggering upper respiratory issues such as stuffy nose. Some COVID-19 patients, however, experience anosmia without any nasal obstruction.

Pinpointing vulnerability

In the current study, Datta and colleagues set out to better understand how sense of smell is altered in COVID-19 patients by pinpointing cell types most vulnerable to SARS-CoV-2 infection.

They began by analyzing existing single-cell sequencing datasets that in total catalogued the genes expressed by hundreds of thousands of individual cells in the upper nasal cavities of humans, mice and nonhuman primates.

The team focused on the gene ACE2, widely found in cells of the human respiratory tract, which encodes the main receptor protein that SARS-CoV-2 targets to gain entry into human cells. They also looked at another gene, TMPRSS2, which encodes an enzyme thought to be important for SARS-CoV-2 entry into the cell.

The analyses revealed that both ACE2 and TMPRSS2 are expressed by cells in the olfactory epithelium — a specialized tissue in the roof of the nasal cavity responsible for odor detection that houses olfactory sensory neurons and a variety of supporting cells.

Neither gene, however, was expressed by olfactory sensory neurons. By contrast, these neurons did express genes associated with the ability of other coronaviruses to enter cells.

The researchers found that two specific cell types in the olfactory epithelium expressed ACE2 at similar levels to what has been observed in cells of the lower respiratory tract, the most common targets of SARS-CoV-2, suggesting a vulnerability to infection.

These included sustentacular cells, which wrap around sensory neurons and are thought to provide structural and metabolic support, and basal cells, which act as stem cells that regenerate the olfactory epithelium after damage. The presence of proteins encoded by both genes in these cells was confirmed by immunostaining.

In additional experiments, the researchers found that olfactory epithelium stem cells expressed ACE2 protein at higher levels after artificially induced damage, compared with resting stem cells. This may suggest additional SARS-CoV-2 vulnerability, but it remains unclear whether or how this is important to the clinical course of anosmia in patients with COVID-19, the authors said.

Datta and colleagues also analyzed gene expression in nearly 50,000 individual cells in the mouse olfactory bulb, the structure in the forebrain that receives signals from olfactory sensory neurons and is responsible for initial odor processing.

Neurons in the olfactory bulb did not express ACE2. The gene and associated protein were present only in blood vessel cells, particularly pericytes, which are involved in blood pressure regulation, blood-brain barrier maintenance and inflammatory responses. No cell types in the olfactory bulb expressed the TMPRSS2 gene.

Smell loss clue

Together, these data suggest that COVID-19-related anosmia may arise from a temporary loss of function of supporting cells in the olfactory epithelium, which indirectly causes changes to olfactory sensory neurons, the authors said.

“We don’t fully understand what those changes are yet, however,” Datta said. “Sustentacular cells have largely been ignored, and it looks like we need to pay attention to them, similar to how we have a growing appreciation of the critical role that glial cells play in the brain.”

The findings also offer intriguing clues into COVID-19-associated neurological issues. The observations are consistent with hypotheses that SARS-CoV-2 does not directly infect neurons but may instead interfere with brain function by affecting vascular cells in the nervous system, the authors said. This requires further investigation to verify, they added.

The study results now help accelerate efforts to better understand smell loss in patients with COVID-19, which could in turn lead to treatments for anosmia and the development of improved smell-based diagnostics for the disease.

“Anosmia seems like a curious phenomenon, but it can be devastating for the small fraction of people in whom it’s persistent,” Datta said. “It can have serious psychological consequences and could be a major public health problem if we have a growing population with permanent loss of smell.”

The team also hope the data can help pave inroads for questions on disease progression such as whether the nose acts as a reservoir for SARS-CoV-2. Such efforts will require studies in facilities that allow experiments with live coronavirus and analyses of human autopsy data, the authors said, which are still difficult to come by. However, the collaborative spirit of pandemic-era scientific research calls for optimism.

“We initiated this work because my lab had a couple of datasets ready to analyze when the pandemic hit, and we published an initial preprint,” Datta said. “What happened after that was amazing, researchers across the globe offered to share and merge their data with us in a kind of impromptu global consortium. This was a real collaborative achievement.”

Co-first authors on the study are David Brann, Tatsuya Tsukahara and Caleb Weinreb. Additional authors include Marcela Lipovsek, Koen Van den Berge, Boying Gong, Rebecca Chance, Iain Macaulay, Hsin-jung Chou, Russell Fletcher, Diya Das, Kelly Street, Hector Roux de Bezieux, Yoon-Gi Choi, Davide Risso, Sandrine Dudoit, Elizabeth Purdom, Jonathan Mill, Ralph Abi Hachem, Hiroaki Matsunami, Darren Logan, Bradley Goldstein, Matthew Grubb and John Ngai.

The study was supported by grants from the National Institutes of Health (grants RO11DC016222 and U19 NS112953) and the Simons Collaboration on the Global Brain. Additional funding information can be found in the full text of the paper.

In a new study published in EBioMedicine, investigators from Brigham and Women’s Hospital conducted a systematic review and meta-analysis, analyzing data from more than 3,000 specimens to compare the three approaches. The team found that sputum testing detected the RNA of the virus that causes COVID-19 at significantly higher rates while oropharyngeal swab testing had lower rates. Regardless of the collection method, the earlier samples were collected after symptoms began, the higher the detection rate.

“The accurate diagnosis of COVID-19 has implications for health care, return-to-work, infection control and public health,” said corresponding author Jonathan Li, MD, a faculty member in the Division of Infectious Diseases at the Brigham. “Our gold standard in and out of the hospital is the nasopharyngeal swab, but there’s a lot of confusion about which sampling modality is best and most sensitive. Our study shows that sputum testing resulted in significantly higher rates of SARS-CoV-2 detection and supports the use of this type of testing as a valuable method for the diagnosis and monitoring of COVID-19 patients.”

Li and his colleagues scoured the literature — both preprints and published papers — for studies that assessed at least two respiratory sampling sites using an NP swab, oropharyngeal swab or sputum. From more than 1,000 studies, they identified 11 that met their criteria. These studies included results from a total of 3,442 respiratory tract specimens.

The team examined how often each collection method produced a positive result. For NP swabs, the rate was 54 percent; for oropharyngeal swabs, 43 percent; for sputum, 71 percent. The rate of viral detection was significantly higher in sputum than either oropharyngeal swabs or NP swabs. Detection rates were highest within one week of symptom onset for all three tests.

“When it comes to testing, the earlier the better, as diagnostic accuracy is improved earlier after symptom onset, regardless of the sampling site,” said Li. “Unlike antibody testing, it’s very rare to have a false positive qPCR test when diagnosing COVID-19 early in the course of the disease using these methods.”

Nasopharyngeal swabs are collected through the nasal cavity; oropharyngeal swabs are collected by inserting a shaft through the mouth; and sputum samples are generally collected by having a patient cough deeply to produce and expel phlegm. Not all patients are able to produce a sputum sample; for such patients, a nasopharyngeal swab may be the best collection method. The meta-analysis included only studies conducted on hospitalized individuals — additional study will be needed of patients who are asymptomatic or have mild symptoms. The current study did not assess alternative testing methods, such as saliva or anterior nasal swabs (taken from the front of the nose). Li and his colleagues at the Brigham are currently working on a project, funded by the Massachusetts Consortium on Pathogen Readiness, to collect and process multiple kinds of samples from patients with COVID-19 to create a resource for researchers.

“The holy grail will be to find a test that is readily acceptable by patients, easy to collect, and highly sensitive,” said Li.

This study was funded in part by the National Institutes of Health (U01AI106701) and the Harvard University for AIDS Research (NIAID 5P30AI060354). Li reports personal fees from Abbvie and from Jan Biotech, outside the submitted work. A co-author reports personal fees from Harvard TH Chan School of Public Health, during the conduct of the study, as well as grants from NIH/NIAID, outside the submitted work.

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The study found that the number of heart transplants performed nationwide dropped 26% during the 8-week period marking the height of the pandemic in the Northeast compared to the prior 8 weeks. The drop in transplants was similar across regions and occurred even in areas with lower infection rates.

The study was published in JAMA Cardiology.

“We had concerns that the availability of ICU beds and ventilators would impact our transplant patients, particularly in the Northeast,” says Ersilia DeFilippis, MD, a postdoctoral clinical fellow in medicine and cardiology at Columbia University Vagelos College of Physicians and Surgeons and the first author of the paper.

“But we were surprised to see a decline in heart transplants in other parts of the country, where there were far fewer COVID-19 cases at that time. Our data show that this pandemic has had far-reaching impacts on the care our patients with advanced heart failure are receiving.”

Heart Transplant Patients Require Many Hospital Resources

Heart transplant patients require a lot of hospital resources, DeFilippis says. “Many patients are sick enough to require hospitalization prior to transplant, often in an intensive care unit, sometimes for weeks or months. Some of these patients are supported on temporary machines to help their hearts pump blood to the body. In addition, the transplant surgery itself requires a ventilator, blood products, and significant personnel. Patients then require intensive care unit monitoring in the immediate post-transplant period.”

At the beginning of the pandemic, clinicians had to weigh the risks of exposing medically fragile patients with heart failure, though well enough to remain at home, to SARS-CoV-2 infection with the risks of delaying a life-changing surgery.

DeFilippis and her colleagues found that many clinicians reacted by taking their patients off the waitlist — a measure typically pursued when a patient encounters a health issue that temporarily or permanently disqualifies them for transplantation but was expanded during the pandemic to include patients at risk of SARS-CoV-2 infection and to accommodate transplant centers that deferred acceptance of donor organs due to the pandemic.

They found that waitlist inactivations increased 75% during the pandemic, driven largely by the Northeast. At the same time, 37% fewer people were placed on heart transplant waitlists during the pandemic, with the most significant decreases occurring in the Northeast, the Great Lakes region, and the Southwest.

In addition, the researchers found that the availability of donor hearts decreased by 26% during the COVID-19 period compared with the pre-COVID-19 period.

“It is possible that limited access to testing for donors as well as restrictions on organ procurement organizations may have contributed to the decrease we observed in donor recovery,” says DeFilippis.

Next, the researchers plan to study the impact of these changes on patient survival while on the transplant waitlist and post-transplant survival.

“It will be similarly important to determine how the pandemic has affected the timing of transplant evaluations and changes in left ventricular assist device implantation. As the pandemic continues, we must be mindful of the effects of these delays on our patients,” says DeFilippis.

The paper, “Trends in US Heart Transplant Waitlist Activity and Volume During the COVID-19 Pandemic,” was published in JAMA Cardiology.

The other authors are Lauren Sinnenberg (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), Nosheen Reza (Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA), Michael M. Givertz (Brigham and Women’s Hospital and Harvard Medical School), Michelle M. Kittleson (Cedars-Sinai Medical Center, Los Angeles, CA), Veli K. Topkara (Columbia University Irving Medical Center, New York, NY), and Maryjane A. Farr (CUIMC).

Cardiovascular disease kills more people in the U.S. than any other condition, accounting for 30% of deaths in 2017. Improvements in cardiovascular mortality began slowing a decade ago and major adverse cardiovascular events such as stroke and myocardial infarction began increasing among adults under age 65. Reasons for these trends are unclear, but experts have proposed causes such as the earlier onset of cardiovascular risk factors, stagnation of preventive care, and a change in health insurance coverage in the U.S. Concerns about the contribution of health insurance to these trends are based on the rapid expansion of HDHPs and previous research about health effects of high out-of-pocket costs.

The study team examined the effects of a transition to a HDHP on the risk of major adverse cardiovascular outcomes such as myocardial infarction and stroke. The study population, drawn from a large national health insurance plan, included individuals with risk factors for cardiovascular disease who were continuously enrolled in low-deductible (<$500) health plans during a baseline year followed by up to 4 years in high-deductible (≥$1000) plans after an employer-mandated switch. The matched control group included individuals with the same risk factors who were contemporaneously enrolled in low-deductible plans. The researchers studied time to first major adverse cardiovascular event, defined as stroke or myocardial infarction.

Study findings show that HDHP members did not experience an increase in major adverse cardiovascular events compared with individuals in low-deductible plans. “Based on previous high-deductible health plan research, we had hypothesized that those with risk factors for cardiovascular disease would experience increases in major adverse cardiovascular events after a switch to high-deductible health plans, but this did not turn out to be the case,” said Frank Wharam, lead author and Associate Professor of Population Medicine at the Harvard Pilgrim Health Care Institute and Harvard Medical School. Dr. Wharam adds, “HDHPs typically include features such as low or no out-of-pocket costs for medications and preventive services. Our study detected small changes in cardiovascular medication use and preventive services which may have protected HDHP members from increased adverse cardiovascular events.

These findings provide a measure of reassurance that HDHP enrollment was not associated with an appreciable increased risk of major adverse cardiovascular outcomes. But researchers caution that policymakers and employers should remain careful in promoting HDHPs among low-income and other vulnerable patients given the potential for adverse financial and health outcomes that this study did not address. Research should also extend follow up time to better assess long-term outcomes and should examine whether people with HDHPs ultimately require more intensive workups and more advanced treatments for cardiovascular events.

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Published online today in Cell Discovery, the research is the latest example of a decoy strategy researchers from the Center for Biotechnology and Interdisciplinary Studies (CBIS) at Rensselear Polytechnic Institute are developing against viruses like the novel coronavirus that spawned the current global health crisis.

The spike protein on the surface of SARS-CoV-2 latches onto the ACE-2 receptor, a molecule on the surface of human cells. Once secured, the virus inserts its own genetic material into the cell, hijacking the cellular machinery to produce replica viruses. But the virus could just as easily be persuaded to lock onto a decoy molecule that offers a similar fit. The neutralized virus would be trapped and eventually degrade naturally.

Previous research has shown this decoy technique works in trapping other viruses, including dengue, Zika, and influenza A.

“We’re learning how to block viral infection, and that is knowledge we are going to need if we want to rapidly confront pandemics,” said Jonathan Dordick, the lead researcher and a professor of chemical and biological engineering at Rensselaer Polytechnic Institute. “The reality is that we don’t have great antivirals. To protect ourselves against future pandemics, we are going to need an arsenal of approaches that we can quickly adapt to emerging viruses.”

The Cell Discovery paper tests antiviral activity in three variants of heparin (heparin, trisulfated heparin, and a non-anticoagulant low molecular weight heparin) and two fucoidans (RPI-27 and RPI-28) extracted from seaweed. All five compounds are long chains of sugar molecules known as sulfated polysaccharides, a structural conformation that the results of a binding study published earlier this month in Antiviral Research suggested as an effective decoy.

The researchers performed a dose response study known as an EC50 — shorthand for the effective concentration of the compound that inhibits 50% of viral infectivity — with each of the five compounds on mammalian cells. For the results of an EC50, which are given in a molar concentration, a lower value signals a more potent compound.

RPI-27 yielded an EC50 value of approximately 83 nanomolar, while a similar previously published and independent in vitro test of remdesivir on the same mammalian cells yielded an EC50 of 770 nanomolar. Heparin yielded an EC50 of 2.1 micromolar, or about one-third as active as remdesivir, and a non-anticoagulant analog of heparin yielded an EC50 of 5.0 micromolar, about one-fifth as active as remdesivir.

A separate test found no cellular toxicity in any of the compounds, even at the highest concentrations tested.

“What interests us is a new way of getting at infection,” said Robert Linhardt, a Rensselaer professor of chemistry and chemical biology who is collaborating with Dordick to develop the decoy strategy. “The current thinking is that the COVID-19 infection starts in the nose, and either of these substances could be the basis for a nasal spray. If you could simply treat the infection early, or even treat before you have the infection, you would have a way of blocking it before it enters the body.”

Dordick added that compounds from seaweed “could serve as a basis for an oral delivery approach to address potential gastrointestinal infection.”

In studying SARS-CoV-2 sequencing data, Dordick and Linhardt recognized several motifs on the structure of the spike protein that promised a fit compatible with heparin, a result borne out in the binding study. The spike protein is heavily encrusted in glycans, an adaptation that protects it from human enzymes which could degrade it, and prepares it to bind with a specific receptor on the cell surface.

“It’s a very complicated mechanism that we quite frankly don’t know all the details about, but we’re getting more information,” said Dordick. “One thing that’s become clear with this study is that the larger the molecule, the better the fit. The more successful compounds are the larger sulfated polysaccharides that offer a greater number of sites on the molecules to trap the virus.”

Molecular modeling based on the binding study revealed sites on the spike protein where the heparin was able to interact, raising the prospects for similar sulfated polysaccharides.

“This exciting research by Professors Dordick and Linhardt is among several ongoing research efforts at CBIS, as well as elsewhere at Rensselaer, to tackle the challenges of the COVID-19 pandemic through novel therapeutic approaches and the repurposing of existing drugs,” said CBIS Director Deepak Vashishth.

“Sulfated polysaccharides effectively inhibit SARS-CoV-2 in vitro” was published in Cell Discovery with the support of the National Research Foundation of Korea. At Rensselaer, Dordick and Linhardt were joined in the research by Paul S. Kwon, Seok-Joon Kwon, Weihua Jin, Fuming Zhang, and Keith Fraser, and by researchers at the Korea Research Institute of Bioscience and Biotechnology in Cheongju, Republic of Korea, and Zhejiang University of Technology in Hangzhou, China.

The scientists analyzed one of the world’s largest collections of known drugs for their ability to block the replication of SARS-CoV-2, and reported 100 molecules with confirmed antiviral activity in laboratory tests. Of these, 21 drugs were determined to be effective at concentrations that could be safely achieved in patients. Notably, four of these compounds were found to work synergistically with remdesivir, a current standard-of-care treatment for COVID-19.

“Remdesivir has proven successful at shortening the recovery time for patients in the hospital, but the drug doesn’t work for everyone who receives it. That’s not good enough,” says Chanda, director of the Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior author of the study. “As infection rates continue to rise in America and around the world, the urgency remains to find affordable, effective, and readily available drugs that can complement the use of remdesivir, as well as drugs that could be given prophylactically or at the first sign of infection on an outpatient basis.”

Extensive testing conducted

In the study, the research team performed extensive testing and validation studies, including evaluating the drugs on human lung biopsies that were infected with the virus, evaluating the drugs for synergies with remdesivir, and establishing dose-response relationships between the drugs and antiviral activity.

Of the 21 drugs that were effective at blocking viral replication, the scientists found:

• 13 have previously entered clinical trials for other indications and are effective at concentrations, or doses, that could potentially be safely achieved in COVID-19 patients.
• Two are already FDA approved: astemizole (allergies), clofazamine (leprosy), and remdesivir has received Emergency Use Authorization from the agency (COVID-19).
• Four worked synergistically with remdesivir, including the chloroquine derivative hanfangchin A (tetrandrine), an antimalarial drug that has reached Phase 3 clinical trials.

“This study significantly expands the possible therapeutic options for COVID-19 patients, especially since many of the molecules already have clinical safety data in humans,” says Chanda. “This report provides the scientific community with a larger arsenal of potential weapons that may help bring the ongoing global pandemic to heel.”

The researchers are currently testing all 21 compounds in small animal models and “mini lungs,” or lung organoids, that mimic human tissue. If these studies are favorable, the team will approach the U.S. Food and Drug Administration (FDA) to discuss a clinical trial(s) evaluating the drugs as treatments for COVID-19.

“Based on our current analysis, clofazimine, hanfangchin A, apilimod and ONO 5334 represent the best near-term options for an effective COVID-19 treatment,” says Chanda. “While some of these drugs are currently in clinical trials for COVID-19, we believe it’s important to pursue additional drug candidates so we have multiple therapeutic options if SARS-CoV-2 becomes drug resistant.”

Screening one of the world’s largest drug libraries

The drugs were first identified by high-throughput screening of more than 12,000 drugs from the ReFRAME drug repurposing collection — the most comprehensive drug repurposing collection of compounds that have been approved by the FDA for other diseases or that have been tested extensively for human safety.

Arnab Chatterjee, Ph.D., vice president of medicinal chemistry at Calibr and co-author on the paper, says ReFRAME was established to tackle areas of urgent unmet medical need, especially neglected tropical diseases. “We realized early in the COVID-19 pandemic that ReFRAME would be an invaluable resource for screening for drugs to repurpose against the novel coronavirus,” says Chatterjee.

The drug screen was completed as rapidly as possible due to Chanda’s partnership with the scientist who discovered the first SARS virus, Kwok-Yung Yuen, M.D., chair of Infectious Diseases at the University of Hong Kong; and Shuofeng Yuan, Ph.D., assistant research professor in the Department of Microbiology at the University of Hong Kong, who had access to the SARS-CoV-2 virus in February 2020.

About the ReFrame library

ReFRAME was created by Calibr, the drug discovery division of Scripps Research, under the leadership of President Peter Shultz, Ph.D., with support from the Bill & Melinda Gates Foundation. It has been distributed broadly to nonprofit collaborators and used to identify repurposing opportunities for a range of disease, including tuberculosis, a parasite called Cryptosporidium and fibrosis.

A global team

The first authors of the study are Laura Riva, Ph.D., a postdoctoral research fellow in the Chanda lab at Sanford Burnham Prebys; and Shuofeng Yuan at the University of Hong Kong, who contributed equally to the study. Additional study authors include Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Lars Pache, Paul De Jesus, Kristina Herbert, Peter Teriete, Yuan Pu, Courtney Nguyen and Andrey Rubanov of Sanford Burnham Prebys; Jasper Fuk-Woo Chan, Jianli Cao, Vincent Poon, Ko-Yung Sit and Kwok-Yung Yuen of the University of Hong Kong; Sebastian Burgstaller-Muehlbacher, Andrew Su, Mitchell V. Hull, Tu-Trinh Nguyen, Peter G. Schultz and Arnab K. Chatterjee of Scripps Research; Max Chang and Christopher Benner of UC San Diego School of Medicine; Luis Martinez-Sobrido, Wen-Chun Liu, Lisa Miorin, Kris M. White, Jeffrey R. Johnson, Randy Albrecht, Angela Choi, Raveen Rathnasinghe, Michael Schotsaert, Marion Dejosez, Thomas P. Zwaka and Adolfo Garcia-Sastre of the Icahn School of Medicine at Mount Sinai; Ren Sun of UCLA; Kuoyuan Cheng of the National Cancer Institute and the University of Maryland; Eytan Ruppin of the National Cancer Institute; Mackenzie E. Chapman, Emma K. Lendy and Andrew D. Mesecar of Purdue University; and Richard J. Glynne of Inception Therapeutics.

Research reported in this press release was supported by the National Institutes of Health (NIH) (U19AI118610, U19AI135972, HHSN272201700060C, GM132024, HHSN272201400008C, HR0011-19-2-0020, U19AI142733), the Department of Defense (DoD) (W81XWH-20-1-0270), the Bill & Melinda Gates Foundation, Dinah Ruch, Susan and James Blair, Richard Yu and Carol Yu, the Shaw Foundation of Hong Kong, Michael Seak-Kan Tong, May Tam Mak Mei Yin, the Health and Medical Research Fund (COVID190121), the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region; the National Program on Key Research Project of China (2020YFA0707500, 2020YFA0707504), Research Grants Council (T11/707/15), the Huffington Foundation, the JPB Foundation, the Open Philanthropy Project (2020-215611 [5384]) and anonymous donors.