Heparin Inhibits SARS-CoV-2, How Mutations Escape Immune Response, Retraining Generic Antibodies: COVID-19 Updates

February 5, 2021

February 5, 2021 I Genetic sequence deletions help SARS-CoV-2 escape antibodies, molecular behavior of COVID-19 drugs, novel drug shows promising broad-spectrum antiviral effect, specific T cell response may prevent severe infection, and the latest COVID-19 forecasts include two new variants. Plus: N439K variant shows two-fold increase in binding affinity and heparin inhibits SARS-CoV-2 spike protein, could be repurposed.


Research News

SARS-CoV-2 escapes immune responses by selectively deleting small bits of its genetic sequence in a recurring pattern of evolution, according to University of Pittsburgh School of Medicine researchers. The team first came across these neutralization-resistant deletions in a sample from an immunocompromised patient, who was infected with SARS-CoV-2 for 74 days before succumbing to the virus. They took a closer look by analyzing a database of SARS-CoV-2 sequences collected from across the world since the beginning of the pandemic. The researchers discovered a pattern of deletions that kept happening in the same spots of the sequence, spots where the virus can tolerate a change in shape without losing its ability to invade cells and replicate. Among the sequences identified as having these deletions was the U.K. variant, B.1.1.7. The authors conclude that SARS-CoV-2 is likely to escape existing vaccines and therapeutics, but the timing of this is uncertain. These findings are published in Science.  DOI:10.1126/science.abf6950

Researchers at the University of Illinois Chicago and California State University at Sacramento have developed a novel strategy that redirects antibodies for other diseases existing in humans to the spike proteins of SARS-CoV-2. In their study, published in the Journal of Physical Chemistry Letters, the team proposes using peptide-based double-faced “booster” inhibitors, with one face binding to the spike proteins of SARS-CoV-2 and the other face binding to generic hepatitis B antibodies. The authors of the study explain that once the SARS-CoV-2 viruses become labeled by the hepatitis B antibodies via intermediate boosters, the viruses will be neutralized, and this universal approach allows a dramatic shortening of the response time upon real infections. They believe that this study could provide guidance in the preparation of generic therapeutics against emerging pathogens with the combined advantages of small-protein and antibody therapies. DOI:10.1021/acs.jpclett.0c03615

Key variants have been identified that help explain the differences between the SARS-CoV-2 virus and Severe Acute Respiratory Syndrome (SARS) and these findings are published in the Frontiers of Molecular Biosciences. When comparing the viruses, the researchers found that both are very similar in sequence and almost identical in structure, but through using computational approaches, they also identified mutations of SARS-CoV that make SARS-CoV-2 significantly more contagious and prone to cause serious infections. They explain that, for example, when SARS-CoV infects or binds to the human cell, it uses several key residues or amino acids to do so, while SARS-CoV-2 uses more residues, which makes it more robust and easier to hijack the human cell. The team identified the most important residues for SARS-CoV-2 to bind to the human cell, which they suggest could be key information for drug development to treat COVID-19 or future outbreaks. DOI:10.3389/fmolb.2020.591873

Department of Energy’s (DOE) Oak Ridge National Laboratory (ORNL) scientists have taken a closer look at the molecular behavior of COVID-19 drugs to better understand the mechanisms by which drug molecules have the potential to mitigate the impact of viral infection. Using neutron scattering instruments at the ORNL Spallation Neutron Source (SNS), the researchers analyzed remdesivir, dexamethasone, and hydroxychloroquine. Their results showed that exposing the drugs to water caused the molecules to become more disordered, similar to how a sugar cube begins to dissolve when wet. When the drug molecules became more disordered as a result of hydration, the methyl groups, which are often included in drug molecules to improve drug potency, required considerably less energy to rotate. These findings suggest that analyzing drug candidates in a hydration-induced disordered state could offer more insight into drug molecule dynamics in the human body, according to the researchers. This study is published in the Journal of Physical Chemistry Letters. DOI:10.1021/acs.jpclett.0c02642

A method to separate the beneficial anti-inflammatory properties of glucocorticoids from some of their unwanted side-effects has been developed by Scripps Research scientists and collaborators. This optimization process, named “ligand class analysis”, has enabled them to engineer two new, drug-like compounds that show steroidal anti-inflammatory action and other specific traits. One compound, SR11466, boosts muscle and energy supply, while the other compound, SR16024, reduces the risk of muscle-wasting and bone loss that is typical of such drugs. This discovery could have positive implications for COVID-19 therapies. The research team believes that the process they developed to refine compounds has implications beyond the improvement of glucocorticoids, as it could also power more selective drug discovery for any number of drugs that work via the cell surface and nuclear receptors to impact signaling and gene transcription in cells. This work is published in Nature Chemical Biology. DOI:10.1038/s41589-020-00719-w

Researchers from the University of Nottingham have uncovered a novel antiviral drug for the potential treatment of COVID-19 and other respiratory viruses. The study, published in Viruses, shows that thapsigargin is a promising broad-spectrum antiviral that was highly effective against SARS-CoV-2, a common cold coronavirus, respiratory syncytial virus (RSV) and the influenza A virus. The research team found that the plant-derived antiviral, at small doses, triggered a robust broad-spectrum host-centered antiviral innate immune response in cell and animal studies. They showed that thapsigargin was effective against viral infection when used before or during active infection and was at least several hundred-fold more effective than current antiviral options. These are just a couple of the promising features of the novel drug, according to the researchers. DOI:10.3390/v13020234

An early functional SARS-CoV-2 specific T cell response may prevent severe infection, according to Duke-NUS Medical School researchers. Their study, published in Cell Reports, investigated the changes in virological and immunological parameters in 12 patients with symptomatic acute COVID-19 infection from onset to recovery or death. They found that patients who experienced only mild symptoms were characterized by an early induction of IFN-y secreting SARS-CoV-2 specific T cells. They also determined that the amount of humoral response does not predict the level of severity with COVID-19 infection. The researchers suggest that T cell monitoring be considered in providing a comprehensive understanding of the immune response against SARS-CoV-2. DOI:10.1016/j.celrep.2021.108728

A new protein that neutralizes SARS-CoV-2 in a human kidney organoid has been developed by Northwestern Medicine scientists. The protein is a variant of angiotensin converting enzyme-2 (ACE2) and modified to intercept the S spike of the coronavirus to trick it into binding to it rather than the real ACE2 receptor in cell membranes. The team is now planning for safety studies of the protein that are needed before Investigational New Drug approval for future studies in COVID-19 patients. This research is published in the Journal of the American Society of Nephrology. DOI:10.1681/ASN.2020101537

University of Bristol researchers have demonstrated how some vitamins, steroids, and antivirals bind to the SARS-CoV-2 spike protein and may reduce infectivity. The team showed that linoleic acid binds to a specific site in the viral spike protein that “locks” the spike into a closed, less infective form. Using computational methods, the researchers then simulated this process and found that dexamethasone might also bind to this site and help reduce viral infectivity in addition to its effects on the human immune system. In further simulations, they identified several drug candidates among available pharmaceuticals and dietary components. Interestingly, their simulations predicted that the fat-soluble vitamins D, K, and A bind to the spike protein in this same way and reduce infectivity. They believe that these findings suggest that a deficiency in these vitamins or pre-existing high cholesterol levels may allow the virus to infect more easily. This study is published in Angewandte Chemie International. DOI:10.1002/anie.202015639

A detailed map of all the molecular activities that are triggered inside lung cells at the onset of SARS-CoV-2 infection has been created by a team of Boston University researchers, which also led to the discovery of 18 existing, FDA-approved drugs that could potentially be repurposed to treat COVID-19. The team simultaneously infected tens of thousands of human lung cells with the SARS-CoV-2 virus, and then tracked precisely what happens in all of those cells during the first few months after infection. The collaborative research team then identified 18 potential drug candidates and found that, experimentally, five of those drugs reduced coronavirus spread in human lung cells by more than 90 percent. They have published this research in Molecular Cell. DOI:10.1016/j.molcel.2020.11.028

University of Texas at Austin scientists have uncovered how remdesivir works to block the copying process of the SARS-CoV-2 virus, and they have published their work in Molecular Cell. The team re-created the process that plays out in a patient who is infected with SARS-CoV-2 in a lab dish and then receives remdesivir. The scientists developed a method for producing fully functional RNA polymerases to copy the viral genetic material. They then added a form of remdesivir. The team was able to capture a 3D snapshot of the molecules using a cryo-electron microscope, just after the reaction with remdesivir was completed. This image allowed them to reconstruct exactly how remdesivir inhibits copying of the virus’s genetic code and its ability to replicate and spread throughout the body. They believe that this finding could also lead to the development of more potent drugs to fight COVID-19 and future potential outbreaks. DOI:10.1016/j.molcel.2021.01.035

Heparin, the common anticoagulant drug, inhibits the SARS-CoV-2 virus spike protein and could be repurposed for the treatment of COVID-19, an international team of researchers has discovered. Using molecular modeling, the researchers showed how heparin targets the spike protein on the surface of SARS-CoV-2, and studies with the live virus showed that unfractionated heparin could inhibit cell infectivity at doses that are similar to those currently used in clinical settings as an anticoagulant. The team also reports that their data strongly supports clinical testing of nebulized unfractionated heparin, since the doses known to be delivered to the lungs would have very strong anti-viral effects. Heparin could be quickly repurposed to help fight COVID-19, or possibly as a prophylactic treatment for high-risk groups, according to the researchers. This work is published in Thrombosis and Haemostasis. DOI:10.1055/s-0040-1721319

A new study, published in Cell, details the effect and molecular mechanisms of the N439K variant of SARS-CoV-2. The N439K mutation is the second most common in the receptor binding domain (RBD) and was first detected in Scotland in March 2020. The researchers determined that viruses carrying this mutation are similar to the wild-type virus in their virulence and ability to spread but can bind to the human ACE2 receptor more strongly. A single amino acid change enables the formation of a new point of contact with the ACE2 receptor, which helps to explain the measured two-fold increase in binding affinity. They also demonstrated that this mutation shows resistance to some individual’s serum antibodies and against many neutralizing monoclonal antibodies, including one that is part of a treatment authorized for emergency use by the U.S. Food and Drug Administration (FDA). The researchers note the challenges in studying SARS-CoV-2 variants, as only a limited amount of sequencing in currently being done (0.4 percent of virus variants have been sequenced), and they highlight the urgent need for broad surveillance and a detailed understanding of the molecular mechanisms of SARS-CoV-2 mutations. DOI:10.1016/j.cell.2021.01.037


Industry News

The Goethe Coronavirus Fund has reached their goal of 5 million euros in donations from over 2,000 contributors. The fund provided researchers at Goethe University and Frankfurt University Hospital with start-up support and more than 40 projects are now being funded, including the coronavirus crisis hotline and studies on the psychological consequences of the pandemic. The latest project supported by the Coronavirus Fund is dedicated to the work situation of healthcare workers and doctors in COVID-19 care in Hessian hospitals who are under particular strain, and the results will be used to make recommendations and concrete options for managers and healthcare workers for workplace health promotion. Press Release

The Bill & Melinda Gates Foundation has granted an award for up to $2.1 million to support the AAVCOVID vaccine program, a novel gene-based vaccine strategy that utilizes an adeno-associated virus vector (AAV). The grant will fund the effort to bring further preclinical validation to the AAV vaccine platform. Preliminary tests of the vaccines’ stability and potency at varying temperatures showed that AAVCOVID candidates remained potent and effective when stored at room temperature for one month. This stability means that the vaccines do not require cold-chain freezer storage and could enable this AAV-based platform to develop a vaccine for COVID-19 and other diseases for developing countries. The AAVCOVID vaccine program was founded at Mass General Brigham. Press Release

The Institute for Health Metrics and Evaluation (IHME) at the University of Washington has released its latest COVID-19 forecasts to include two new virus variants. The forecasts show the possibility of a spring spike in deaths with these new variants, and researchers say that mask-wearing and continued social distancing will remain critical despite vaccine rollout. They estimate that the United States will see approximately 654,000 total deaths by May 1 and a resurgence of the virus in the spring in some states, assuming widespread transmission of the B.1.351 variant from South Africa and mobility returning to pre-pandemic levels in the vaccinated. Without the transmission of B.1.351, the forecast in the U.S. drops to 595,000 deaths by May 1, which is an increase of about 26,000 from last week’s predictions. They say that this increase is driven by taking into account that some states are not re-imposing social distancing mandates even as daily death rates rise. Press Release