A novel computational drug screening strategy, combined with lab experiments, suggest that pralatrexate, a chemotherapy medication originally developed to treat lymphoma, could potentially be repurposed to treat COVID-19. Haiping Zhang, PhD, of the Shenzhen Institutes of Advanced Technology in Shenzhen, China, and colleagues presented these findings in the open-access journal PLOS Computational Biology in an article published on December 31, 2020. The article is titled “A Novel Virtual Screening Procedure Identifies Pralatrexate As Inhibitor of SARS-CoV-2 Rdrp and It Reduces Viral Replication in Vitro.” With the COVID-19 pandemic causing illness and death worldwide, better treatments are urgently needed. One shortcut could be to repurpose existing drugs that were originally developed to treat other conditions. Computational methods can help identify such drugs by simulating how different drugs would interact with SARS-CoV-2, the virus that causes COVID -19. To aid virtual screening of existing drugs, Dr. Zhang and colleagues combined multiple computational techniques that simulate drug-virus interactions from different, complementary perspectives. They used this hybrid approach to screen 1,906 existing drugs for their potential ability to inhibit replication of SARS-CoV-2 by targeting a viral protein called RNA-dependent RNA polymerase (RdRP). The novel screening approach identified four promising drugs, which were then tested against SARS-CoV-2 in lab experiments. Two of the drugs, pralatrexate and azithromycin, successfully inhibited replication of the virus. Further lab experiments showed that pralatrexate more strongly inhibited viral replication than did remdesivir, a drug that is currently used to treat some COVID -19 patients.
On Decembr 30, 2020, CytoDyn Inc. (OTC.QB: CYDY), a late-stage biotechnology company developing Vyrologix™ (leronlimab) (PRO 140), a CCR5 antagonist with the potential for multiple therapeutic indications, announced that a research manuscript submitted by first author Nicholas J. Agresti, MD, has been accepted for publication in the Journal of Translational Autoimmunity. The research findings of Dr. Agresti and colleagues were based on four critically ill COVID-19 patients treated with leronlimab under an FDA-approved emergency investigational new drug (eIND) application. All four were on mechanical ventilators and fully recovered following leronlimab treatment. Dr. Agresti is a gastroenterologist in the Southeast Georgia Health System. The manuscript (Ms. No. JTAUTO-D-20-00043R1) is entitled “Disruption of CCR5 Signaling to Treat COVID-19-Associated Cytokine Storm: Case Series of Four Critically Ill Patients Treated with Leronlimab.” The accepted research paper can be accessed here (d1io3yog0oux5.cloudfront.net/cytodyn/files/pages/cytodyn/db/256/content/JTAUTO-D-20-00043_R1+_3__1_.pdf). Additional authors on the paper included Bruce Patterson, MD, CEO and Founder, Incell Dx; Kabir Mody, MD, Mayo Clinic; Jacob Lalezari, MD, CytoDyn advisor, now CMO at Virion; Jonah B. Sacha, PhD, Vaccine and Gene Therapy Institute and Oregon National Primate Research Center, Oregon; Harish Seethamraju, MD, Medical Director, Advanced Lung Failure and Lung Transplant, Montefiore Medical Center; Seth Gross, MD, NYU Langone Gastroenterology Associates; Scott Kelly, MD, CMO, CytoDyn; Nader Pourhassan, PhD, President and CEO, CytoDyn, and Kush Dody, MBBS, Vice President, Clinical Operations, Amarex Clinical Research, among others. Dr. Agresti stated:
Boosting immune system T cells to effectively attack solid tumors, such as breast cancers, can be done by adding a small molecule to a treatment procedure called chimeric antigen receptor-T (CAR-T) cell therapy (en.wikipedia.org/wiki/Chimeric_antigen_receptor_T_cell), according to a study by researchers at the University of North Crolina (UNC) Lineberger Comprehensive Cancer Center. The boost helps recruit more immune cells into battle at the tumor site. The findings were published online on December 31, 2020 in the Journal of Experimental Medicine. The JEM article is titled “STING Agonist Promotes CAR T Cell Trafficking and Persistence in Breast Cancer.” CAR-T immunotherapy, in which T cells are modified in the laboratory to express chimeric antigen receptors, CARs, that in turn target surface proteins on cancer cells, has been most effective in the treatment of patients with B-cell leukemia or lymphoma. But this new research, conducted in mouse models, points to the potential for using CAR-T therapy effectively against solid tumors as well. “We know that CAR T cells are safe for patients with solid tumors but so far they have not been able to cause significant tumor regression in the overwhelming majority of people treated,” said Jonathan S. Serody, MD, the Elizabeth Thomas Professor of Medicine, Microbiology, and Immunology and Director of the Immunotherapy Program at UNC Lineberger. “Now we may have a new approach to make CAR T cells work in solid tumors, which we think could be a game-changer for therapies aimed at an appreciable number of cancers.” Dr. Serody is the paper’s corresponding author and Nuo Xu, PhD, formerly a graduate student at UNC Lineberger and UNC School of Medicine, is the first author.
A peer-reviewed paper published online on December 30, 2020 in The New England Journal of Medicine provides data from the much-anticipated COVE study, which evaluated mRNA-1273, a vaccine candidate against COVID-19 manufactured by Moderna, Inc. Results from the primary analysis of the study, which will continue for two years, provide evidence that the vaccine can prevent symptomatic infection. Among the more than 30,000 participants randomized to receive the vaccine or a placebo, 11 of those in the vaccine group developed symptomatic COVID-19 compared to 185 participants who received the placebo, demonstrating 94.1 percent efficacy in preventing symptomatic COVID-19. Cases of severe COVID-19 occurred only in participants who received the placebo. Brigham and Women’s Hospital served as a site for the trial as part of the COVID-19 Prevention Network (CoVPN), funded by the National Institutes of Health. In addition, Lindsey Baden, MD, an infectious diseases specialist at the Brigham and an expert in vaccine development for viral diseases, served as Co-Principal Investigator for the study and lead author of the paper. The open-access NEJM article is titled “Efficacy and Safety of mRNA-1273 SARS-CoV-2 Vaccine.” “Our work continues. Over the next months, we’ll have increasing amounts of data to better define how this vaccine works, but the results so far show a 94.1 percent efficacy. These numbers are compelling,” said Dr. Baden. “And, importantly, the data suggest protection from severe illness, indicating that the vaccine could have an impact on preventing hospitalizations and deaths, at least in the first several months post-vaccination.”
One of the physiopathological characteristics of COVID-19 that has most baffled the scientific and medical community is what is known as “silent hypoxemia” or “happy hypoxia.” Patients suffering this phenomenon, the causes of which are still unknown, have severe pneumonia with markedly decreased arterial blood oxygen levels (known as hypoxemia). However, they do not report dyspnea (subjective feeling of shortness of breath) or increased breathing rates, which are usually characteristic symptoms of people with hypoxemia from pneumonia or any other cause. Patients with “silent hypoxemia” often suffer a sudden imbalance, reaching a critical state that can be fatal. Normally, individuals (healthy or sick) with hypoxemia report a feeling of shortness of breath and a higher breathing rate, thus increasing the body’s uptake of oxygen. This reflex mechanism depends on the carotid body. This small organ, located on either side of the neck next to the carotid artery, detects the drop in blood oxygen and sends signals to the brain to stimulate the respiratory center. A group of researchers from the Seville Institute of Biomedicine – IBiS/University Hospitals Virgen del Rocío y Macarena/CSIC/University of Seville, led by Dr. Javier Villadiego, Dr. Juan José Toledo-Aral, and Dr. José López-Barneo, specialists in the physiopathological study of the carotid body, have suggested in the journal Function, that “silent hypoxemia” in COVID-19 cases could be caused by this organ (carotid body) being infected by the coronavirus (SARS-CoV-2).
On Decembr 29, 2020, Capricor Therapeutics, Inc. (NASDAQ: CAPR), a clinical-stage biotechnology company focused on the discovery, development, and commercialization of first-in-class cell- and exosome-based therapeutics for the treatment and prevention of a variety of diseases and disorders, announced today that the independent Data and Safety Monitoring Board (DSMB) has completed its safety review for Capricor’s Phase II INSPIRE study (www.clinicaltrials.gov/ct2/show/NCT04623671?spons=capricor&draw=2&rank=1). The DSMB recommended that the study continue as designed with Capricor’s cardiac cell therapy, CAP-1002, for treating patients with severe COVID-19. In addition, an independent prespecified review of the safety data was conducted on an initial group of INSPIRE patients and the study is continuing according to the study protocol. “As hospitalizations continue to steadily increase heading into the New Year, the DSMB’s recommendation is vital as we continue this study to potentially help patients who are at a high risk for significant morbidity or even death,” said Linda Marbán, PhD, Capricor’s President and CEO. “Given that CAP-1002 polarizes macrophages to an anti-inflammatory, healing immunomodulatory phenotype, it may subsequently attenuate the effects of the cytokine storm associated with severe COVID-19.”
On Decembr 30, 2020, Codiak BioSciences, Inc. (NASDAQ: CDAK), a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, announced that the primary objectives were met in the initial part of its Phase 1 trial, which evaluated a single ascending dose of exoIL-12 in healthy volunteers. In this randomized, placebo controlled, double-blind study, exoIL-12 demonstrated a favorable safety and tolerability profile, with no local or systemic treatment-related adverse events and no detectable systemic exposure of IL-12. “This is an important milestone, as these results show that exoIL-12 acts in humans as we had expected, based on our preclinical evaluations. The safety and tolerability profile observed here support the target profile that we are hoping to achieve with this candidate,” said Benny Sorensen, MD, PhD, Senior Vice President and Head of Clinical Development, Codiak. “We’re looking forward to advancing exoIL-12 into the multi-dose part of the study in cutaneous T-cell lymphoma patients and presenting the detailed results from the healthy volunteer part of this study at an upcoming medical conference.”
N-aryl-C-nitroazoles are an important class of heterocyclic compounds. They are used as pesticides and fungicides. However, these substances could be toxic to humans and cause mutations. As they are not frequently used, there is little data about them in the medicinal chemistry literature. However, it has been suggested recently that the groups of compounds that are traditionally avoided may help to fight pathogenic bacteria. Yet, to reduce toxic effects, a great amount of work must be carried out at the molecular level, accurate optimization of the molecular environment of the nitro-heteroaromatic “warhead.” The validity of this approach was demonstrated in the early 2000s through the development of anti-tuberculosis drugs delamanid and pretomanid, currently approved for medical use. They act like prodrugs, that is, the substance itself is inactive, but acquires effective new properties when it enters the human body. In terms of the new work described here, scientists from the Immanuel Kant Baltic Federal University in Kaliningrad, together with colleagues from St. Petersburg State University, the L. Pasteur Research Institute of Epidemiology and Microbiology, and the Research Institute of Phthisiopulmonology, all in St. Petersburg (photo), are looking for new effective antibacterial drugs, studying various nitrogen heteroaromatic compounds with a nitro group which might be used in medicine further. The compound OTB-021 was found to work well against drug-sensitive strains of tuberculosis pathogens, but was powerless against strains of pathogens that belong to the so-called ESKAPE panel.
Thanks to the marine worm Platynereis dumerilii (image), an animal whose genes have evolved very slowly, scientists from the French National Centre for Scientific Research (CNRS), Université de Paris, and Sorbonne Université, in association with others at the University of Saint Petersburg and the University of Rio de Janeiro, have shown that while hemoglobin appeared independently in several species, it actually descends from a single gene transmitted to all by their last common ancestor. These findings were published online on December 29, 2020 in BMC Evolutionary Biology. The open-access article is titled “Globins in the Marine Annelid Platynereis dumerilii Shed New Light on Hemoglobin Evolution in Bilaterians.” Having red blood is not peculiar to humans or mammals. This color comes from hemoglobin, a complex protein specialized in transporting the oxygen found in the circulatory system of vertebrates, but also in annelids (a worm family whose most famous members are earthworms), molluscs (especially pond snails), and crustaceans (such as daphnia or “water fleas”). It was thought that for hemoglobin to have appeared in such diverse species, it must have been “invented” several times during evolution. But recent research has shown that all of these hemoglobins, thought to have been born “independently,” actually derive from a single ancestral gene. Researchers from the Institut Jacques Monod (CNRS/Université de Paris), the Laboratoire Matière et Systèmes Complexes (CNRS/Université de Paris), the Station Biologique de Roscoff (CNRS/Sorbonne Université), the Universities of Saint Petersburg (Russia) and Rio de Janeiro (Brazil), conducted this research on Platynereis dumerilii, a small marine worm with red blood.
On December 28, 2020, Novavax, Inc. (Nasdaq: NVAX), a late-stage biotechnology company developing next-generation vaccines for serious infectious diseases, announced initiation of PREVENT-19, its pivotal Phase 3 study in the United States and Mexico to evaluate the efficacy, safety and immunogenicity of NVX-CoV2373, the company’s COVID-19 vaccine candidate. The trial builds on research from Phase 1/2 studies demonstrating that the vaccine provoked a robust immune response, generated highly neutralizing antibodies against the virus, and was generally well-tolerated. “With the COVID-19 pandemic raging around the globe, this trial is a critical step in building the global portfolio of safe and effective vaccines to protect the world’s population,” said Stanley C. Erck, MBA, President and Chief Executive Officer, Novavax. “We thank our colleagues and partners who continue to work with us to urgently advance our commercial-scale manufacturing processes, and we are grateful for the hard work and assistance from Operation Warp Speed, the U.S. FDA, and the government of Mexico on this program.” NVX-CoV2373 contains a full-length, prefusion spike protein made using Novavax’ recombinant nanoparticle technology and the company’s proprietary saponin-based Matrix-M™ adjuvant. The purified protein is encoded by the genetic sequence of the SARS-CoV-2 spike (S) protein and is produced in insect cells. It can neither cause COVID-19 nor can it replicate, is stable at 2°C to 8°C and is shipped in a ready-to-use liquid formulation that permits distribution using standard vaccine supply chain channels.