AI Predicts New COVID-19 Drugs, New Commercial COVID-19 Command Center
By Bio-IT World Staff
May 8, 2020 New research on COVID-19 treatments and vaccines from worldwide researchers at Northwestern University, Erasmus MC University Medical Center, the Russian Academy of Sciences, the University of Southern California and more. Saama Technologies and iNDX.Ai and launched the COVID-19 Command Center, and AI and supercomputing technologies flag new drugs. We round up the week’s research and industry news for COVID-19.
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Literature Updates
Northwestern University researchers have developed a tool, powered by artificial intelligence (AI), to speed up the search for COVID-19 treatments and vaccines by prioritizing resources for the most promising studies and ignoring research that is unlikely to yield benefits. Scientists have traditionally relied on the Defense Advanced Research Projects Agency's Systematizing Confidence in Open Research and Evidence (DARPA SCORE) program, which is based on expert opinions about how likely research studies are to be replicable—a process that takes an average of 314 days. As reported in Proceedings of the National Academy of Sciences, the machine model is just as accurate as the human scoring system at making such predictions and takes only minutes to review the number of scientific papers now being produced at an unprecedented rate. In fact, the algorithm may be even more accurate than human-scoring predictions because it considers more of the narrative of studies and subconsciously meaningful word-choice patterns versus mostly relational statistics. Paired together, the combined human-machine approach predicts which findings will be replicable with even greater accuracy than either method on its own. DOI: 10.1073/pnas.1909046117
Researchers from Hubrecht Institute in Utrecht, Erasmus MC University Medical Center Rotterdam, and Maastricht University in The Netherlands have found that SARS-CoV-2 can infect cells of the intestine and multiply there. They have also successfully propagated the virus in vitro and monitored the response of intestinal cells to the virus, providing a new cell culture model for the study of COVID-19. Their findings, published in Science, could explain why about one-third of COVID-19 patients experience gastrointestinal symptoms such as nausea and diarrhea, and the virus often can be detected in stool samples long after respiratory symptoms have been resolved. This suggests that the virus can also spread via fecal-oral transmission. The respiratory and gastrointestinal organs both harbor ACE2 receptors, through which SARS-CoV-2 can enter cells. The researchers investigated cell response to the virus with RNA sequencing, revealing that interferon-stimulated genes (known to combat viral infection) get activated. They also cultured their organoids in different conditions and discovered that SARS-CoV-2 infected cells with both high and low levels of the ACE2 receptor. DOI: 10.1126/science.abc1669
A new study out of the Keck School of Medicine of USC suggests that temporarily suppressing the body's immune system during the early stages of COVID-19 could help a patient avoid severe symptoms. The research, published in the Journal of Medical Virology, shows that an interaction between the body's two main lines of defense—the innate immune response that starts right after an infection and the adaptive immune response that kicks in days later if any virus remains—may be causing the immune system to go into overdrive in some patients. Researchers used a common mathematical model developed to understand the dynamics of viral infections to examine how the two immune responses work in COVID-19 patients compared to patients who have the flu. They discovered that with COVID-19 the adaptive immune response may kick in before the target cells are depleted, slowing down the infection and interfering with the innate immune response's ability to kill off most of the virus quickly. This longer duration of viral activity may lead to a cytokine storm, killing healthy cells. Interaction of the two immune responses might explain why some COVID-19 patients experience a resurgence of the disease after an apparent easing of symptoms. Small studies in China, including a recent one of COVID-19 patients, associate use of immunosuppressants such as corticosteroids to better results. DOI: 10.1002/jmv.25866
New high-resolution cryo-EM structural information about remdesivir illuminates the mechanism the antiviral drug uses to interrupt RNA replication and shut down viral reproduction, which may inform efforts to develop new and more potent therapies that employ a similar mechanism. In Science, a team of Chinese scientists report that remdesivir bound to both a molecule of RNA and to the viral polymerase, which plays a central role in the replication of SARS-CoV-2 and is a primary target for fighting the virus. In its active form, the drug mimics the structure of adenosine, a nucleoside that is incorporated into RNA during replication. When added to a new RNA molecule, it blocks further synthesis of viral RNA. DOI: 10.1126/science.abc1560
Researchers at Utrecht University, Erasmus Medical Center and Harbour BioMed report in Nature Communications that they have identified a “fully human” monoclonal antibody that prevents the SARS-CoV-2 virus from infecting cultured cells. They used a preexisting collection of SARS-CoV antibodies to identify the one that also neutralizes infection by the COVID-19 virus. The identified antibody binds to a domain that is conserved in both SARS-CoV and SARS-CoV-2, and this cross-neutralizing feature suggests it may have potential in mitigation of diseases caused by future-emerging related coronaviruses. The antibody was generated using Harbour BioMed's H2L2 transgenic mouse technology. DOI: 10.1038/s41467-020-16256-y
Infection researchers from the German Primate Center have identified starting points for COVID-19 vaccine development and therapy. The unusual activation sequence harbored by the SARS-CoV-2 spike protein is cleaved by the cellular enzyme furin and important for the infection of lung cells, they report in Molecular Cell. This cleavage event is also important for the fusion of infected cells with non-infected cells, which might allow the virus to spread in the body without leaving the host cell. Results suggest that inhibition of furin should block the spread of SARS-CoV-2 in the lung. SARS-CoV-2 variants, in which the activation sequence for furin has been removed, could be used as a basis for the development of live attenuated vaccines that trigger a strong immune response. SARS-CoV-2 carries an activation sequence at the so-called S1/S2 cleavage site, the focus of the search for coronaviruses in wildlife that have the potential to spread efficiently in humans as well as a possible marker for human-to-human transmissibility. DOI: 10.1016/j.molcel.2020.04.022
Russian scientists from the Institute of Gene Biology of the Russian Academy of Sciences, the State Virology and Biotechnology Research Center VECTOR and Belgorod University are developing SARS-CoV-2-sensitive mice to be used as a murine model in tests of potential COVID-19 vaccines and drugs, a two-step concept described in Research Results and Pharmacology. The mice are first made biologically safe for routine laboratory practice and then to experience symptoms and pathogenesis as human-like as possible. First results could be available by June 2020. The key difference between the new model and existing ones is biological safety; animals will become sensitive to SARS-CoV-2 only after activation in conditions of a virology laboratory that make it possible to nullify the contagion risk for the staff during a pandemic. To obtain mice with human-like COVID-19 symptoms and pathology, the researchers will introduce human ACE2 and TMPRSS2 genes (involved in virus entry into cells) to the murine genome under the mice's own Tmprss2 promoter. Crossbreeding will only happen in specialized labs to prevent the novel line of mice from becoming an infection “reservoir” in ordinary labs, researchers explain. DOI: 10.3897/rrpharmacology.6.53633
Researchers at the University of Missouri have identified four possible treatments for COVID-19. Using computer-aided drug design, they examined the effectiveness of broad-spectrum RNA polymerase inhibitors remdesivir, 5-fluorouracil, ribavirin and favipiravir in treating COVID-19 and found that all of them were effective in inhibiting the coronavirus' RNA proteins from making genomic copies of the virus. The added benefit of using these antivirals is that a significant wealth of knowledge already exists regarding their administration, efficacy, toxicity and side effects in humans, which can speed up clinical trials in COVID-19 patients. Results published in Pathogens. DOI: 10.3390/pathogens9050320
Korean researchers have screened 48 FDA-approved drugs against SARS-CoV-2 and found that two— anti-helminthic drug niclosamide and inhaled corticosteroid ciclesonide—seem promising. They tested the drugs in a cell line developed from kidney cells of the African Green Monkey, which are commonly used to grow viruses for vaccine production. Niclosamide’s broad-spectrum antiviral effect, notably against SARS- and MERS-CoV, has been well documented in the literature but a downside is low absorption. Despite its substantially lower antiviral potency, ciclesonide has reportedly treated three COVID-19 patients and its molecular target is a viral protein called Nsp15. The proven anti-inflammatory activity of ciclesonide may make it a potent drug for the control of SARS-CoV-2 infection, dampening or preventing the cytokine storms that can kill COVID-19 patients. Findings appeared in Antimicrobial Agents and Chemotherapy. DOI: 10.1128/AAC.00819-20
The brain may be a new therapeutic target for improving breathing following lung injury in COVID-19, speeding the process of weaning patients from mechanical ventilators, according to research published in the Journal of Physiology. The new study examining rats—including those with acute lung injury and its most severe form, acute respiratory distress syndrome (ARDS)—indicates that injury may have a lasting impact on the central control of respiration. Characteristics of the pathologic breathing pattern remained even when the lungs were removed; in addition, inflammation was evident in the part of the brain that generates the breathing pattern. Targeting that brain region might be an important therapy for weaning patients from ventilatory support, researchers say. Treating conscious rodents with non-steroidal anti-inflammatory drugs within the central nervous system also reduced neural inflammation and minimized the effects of lung injury, suggesting brainstem circuits play a role in the pathophysiology and potential recovery of the respiratory system following lung injury and ARDS. DOI: 10.1113/JP279177
By analyzing virus genomes from over 7,500 people infected with COVID-19, a research team led by University College London Genetics Institute has characterized patterns of diversity of the SARS-CoV-2 virus genome, offering clues to direct drugs and vaccine targets. The study identified close to 200 recurrent genetic mutations in the virus, which appear to have independently occurred more than once, highlighting how it may be adapting and evolving to its human hosts. Researchers found that a large proportion of the global genetic diversity of SARS-CoV-2 is found in all hardest-hit countries, suggesting extensive global transmission from early in the epidemic and the absence of single “Patient Zeroes” in most countries. The findings published in Infection, Genetics and Evolution and further establish the virus only emerged in late 2019 before quickly spreading across the globe. It remains unknown whether SARS-CoV-2 is becoming more lethal and contagious or less so. But identified mutations were not evenly distributed across the virus genome and the parts with few genetic changes might be better targets for drug and vaccine development. An interactive, open-source online application allows researchers across the globe to review the virus genomes and apply similar approaches. DOI: 10.1016/j.meegid.2020.104351
Industry News
Saama Technologies and iNDX.Ai and launched the COVID-19 Command Center based on a combination of Saama’s Life Science Analytics Cloud (LSAC) and iNDX.Ai’s iCore Platform, is a purpose-built, therapeutic area-specific data analytics platform. The COVID-19 Command Center was created to provide sponsors pursuing in-house COVID-19 clinical development efforts only with the same powerful, state-of-the-art, AI-powered data analytics platform being used by the EndPandemic National Data Consortium (of which both companies are members). The COVID-19 Command Center includes patient data from ongoing COVID-19 clinical trials in China, South Korea, and the U.S. with nearly 8,500 patients, including over 3,000 positive cases and delivers all the multiomics and clinical data analytics needed to manage COVID-19 clinical studies. From preclinical development to approval, researchers can optimize study design, patient selection, site activation, and scientific analysis by dynamically visualizing, analyzing, and interrogating data faster than ever before. Press release.
Researchers of the international consortium iCAIR are striving to develop novel anti-infective agents to treat or prevent clinically significant respiratory diseases caused by viruses, fungi and bacteria–and recently started a project to develop medications against SARS-CoV-2. In the iCAIR consortium (Fraunhofer International Consortium for Anti-Infective Research) Fraunhofer ITEM is collaborating with Griffith University's Institute for Glycomics (IfG) in Australia, the Hannover Medical School (MHH; Germany), and TWINCORE, a joint venture between MHH and Helmholtz Centre for Infection Research (Germany) to develop new, urgently needed agents against respiratory tract infections. The researchers are first screening substance libraries for drug candidates that stop SARS-CoV-2 infection using substance libraries available at IfG and HZI. Press release.
Research based on extensive calculations using the MOGON II supercomputer at Johannes Gutenberg University Mainz (JGU, Germany) has identified several drugs approved for treating hepatitis C as potential candidates against COVID-19. As the JGU researchers explained in a paper published on the World Health Organization website, they had simulated the way that about 42,000 different substances listed in open databases bind to certain proteins of SARS-CoV-2 and thereby inhibit the penetration of the virus into the human body or its multiplication. This represented the first use of molecular docking (a recognized computer simulation method) with SARS-CoV-2. After making more than 30 billion single calculations within two months, researchers found that compounds from simeprevir, paritaprevir, grazoprevir and velpatasvir have a high affinity to bind SARS-CoV-2 very strongly and may therefore be able to prevent infection. SARS-CoV-2 and the hepatitis C are both single-stranded RNA viruses, they note. Lonicera japonica, a natural substance from the Japanese honeysuckle that has been used in Asia against various other diseases, might be another strong candidate against SARS-CoV-2, they add. Press release.
Massachusetts Eye and Ear and Massachusetts General Hospital, members of Mass General Brigham, have announced progress in testing and development of AAVCOVID, a novel gene-based vaccine candidate against SARS-CoV2. The AAVCOVID Vaccine Program uses adeno-associated viral (AAV) vector, a clinically established gene transfer technology leveraging the properties of a harmless viral carrier, to deliver genetic sequences of the SARS-CoV-2 spike antigen so the body can develop an immune response. Tests are currently underway in animal models, and initial manufacturing activities have begun. Based on preclinical findings, one or more candidates will advance into the clinical phase of testing in humans later this year. Researchers say AAV is a superior technology for safe and efficient gene delivery and the unique technologies being applied support the potential for a potent immunity to be induced to SARS-CoV-2 from a single injection. A draft of a vaccine can be developed in weeks by harnessing the power of molecular biology. Press release.