March 13, 2020


The Convalescent Sera Option for Containing COVID-19  

  

As of early 2020, humanity is confronting a pandemic in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 causes coronavirus disease, abbreviated as COVID-19. At the time of this writing, SARS-CoV-2 is spreading in multiple countries, threatening a pandemic that will affect billions of people. This virus appears to be a new human pathogen. Currently there are no vaccines, monoclonal antibodies (mAbs), or drugs available for SARS-CoV-2, although many are in rapid development and some may be available in a short time. This Viewpoint argues that human convalescent serum is an option for prevention and treatment of COVID-19 disease that could be rapidly available when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum. Passive antibody therapy Passive antibody therapy involves the administration of antibodies against a given agent to a susceptible individual for the purpose of preventing or treating an infectious disease due to that agent. In contrast, active vaccination requires the induction of an immune response that takes time to develop and varies depending on the vaccine recipient. Thus, passive antibody administration is the only means of providing immediate immunity to susceptible persons.  

March 11, 2020


A Data-Driven Drug Repositioning Framework Discovered a Potential Therapeutic Agent Targeting COVID-19 


    

The global spread of SARS-CoV-2 requires an urgent need to find effective therapeutics for the treatment of COVID-19. We developed a data-driven drug repositioning framework, which applies both machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and tran-scriptome data to discover the potential drug candidates against SARS-CoV-2. The retrospective study using the past SARS-CoV and MERS-CoV data demonstrated that our machine learning based method can successfully predict effective drug candidates against a specific coronavirus. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 is able to suppress the CpG-induced IL-6 production in peripheral blood mononuclear cells, suggesting that it may also have anti-inflammatory effect that is highly relevant to the prevention immunopathology induced by SARS-CoV-2 infection. Further pharma- cokinetic and toxicokinetic evaluation in rats and monkeys showed a high concentration of CVL218 in lung and observed no apparent signs of toxicity, indicating the appealing potential of this drug for the treatment of the pneumonia caused by SARS-CoV-2 infec- tion. Moreover, molecular docking simulation suggested that CVL218 may bind to the N-terminal domain of nucleocapsid (N) protein of SARS-CoV-2, providing a possible model to explain its antiviral action. We also proposed several possible mechanisms to explain the antiviral activities of PARP1 inhibitors against SARS-CoV-2, based on the data present in this study and previous evidences reported in the literature. In sum- mary, the PARP1 inhibitor CVL218 discovered by our data-driven drug repositioning framework can serve as a potential therapeutic agent for the treatment of COVID-19. 

March 10, 2020


Old Drugs for Newly Emerging Viral Disease, COVID-19: Bioinformatic Prospective 


Coronavirus (COVID-19) outbreak in late 2019 and 2020 comprises a serious and more likely a pandemic threat worldwide. Given that the disease has not approved vaccines or drugs up to now, any efforts for drug design and or clinical trails of old drugs based on their mechanism of action are worthy and creditable in such circumstances. Experienced docking experiments using the newly released coordinate structure for COVID-19 protease as a receptor and thoughtfully selected chemicals among antiviral and antibiotics drugs as ligands may be leading in this context. We selected nine drugs from HIV-1 protease inhibitors and twenty-one candidates from anti bronchitis drugs based on their chemical structures and enrolled them in blind and active site-directed dockings in different modes and in native-like conditions of interactions. Our findings suggest the binding capacity and the inhibitory potency of candidates are as follows Tipranavir>Indinavir>Atazanavir>Darunavir>Ritonavir>Amprenavir for HIV-1 protease inhibitors and Cefditoren>Cefixime>Erythromycin>Clarithromycin for anti bronchitis medicines. The drugs bioavailability, their hydrophobicity and the hydrophobic properties of their binding sites and also the rates of their metabolisms and deactivations in the human body are the next determinants for their overall effects on viral infections, the net results that should survey by clinical trials to assess their therapeutic usefulness for coronavirus infections. 

March 9, 2020


In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) 


Hydroxychloroquine was found to be more potent than chloroquine at inhibiting SARS-CoV-2 in vitro. Hydroxychloroquine sulfate 400 mg given twice daily for 1 day, followed by 200 mg twice daily for 4 more days is recommended to treat SARS-CoV-2 infection. 

March 9, 2020


Efficacy of Chloroquine and Lopinavir/Ritonavir in mild/general COVID-2019: a prospective, open- label, multicenter randomized controlled clinical study 


  

The outbreak of novel coronavirus pneumonia is very serious, and no effective antiviral treatment has been confirmed. The fresh drug research and development cycle is too long to meet clinical emergency needs, and "old drugs and brand new applications" have a huge therapeutic potential. During our previous treatment, we found that the lopinavir/ritonavir treatment recommended in the Fifth edition of the treatment plan had little effect. Earlier studies have shown that chloroquine can inhibit coronavirus replication through multiple mechanisms. Our previous use of chloroquine to treat patients with SARS-CoV-2(novel coronavirus)-infected pneumonia has a higher negative rate of nucleic acid in throat swabs within 5 days after administration than that using lopinavir/ritonavir. However, the half-life and side effects of chloroquine vary greatly among individuals. We plan to conduct a prospective, open-label, multicenter randomized controlled, comprehensive treatment clinical study. Our study is a prospective, open-label, multicenter randomized controlled, comprehensive treatment clinical study to evaluate the efficacy and safety of chloroquine phosphate and lopinavir/ritonavir in patients with mild/general COVID-2019. The results of this study will provide valuable clinical evidence for the treatment of novel coronavirus pneumonia. 

March 9, 2020


Research and Development on Therapeutic Agents and Vaccines for COVID-19 and Related Human Coronavirus Diseases 


Since the outbreak of the novel coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, this disease has spread rapidly around the globe. Considering the potential threat of a pandemic, scientists and physicians have been racing to understand this new virus and the pathophysiology of this disease to uncover possible treatment regimens and discover effective therapeutic agents and vaccines. To support the current research and development, CAS has produced a special report to provide an overview of published scientific information with an emphasis on patents in the CAS content collection. It highlights antiviral strategies involving small molecules and biologics targeting complex molecular interactions involved in coronavirus infection and replication. The drug-repurposing effort documented herein focuses primarily on agents known to be effective against other RNA viruses including SARS-CoV and MERS-CoV. The patent analysis of coronavirus- related biologics includes therapeutic antibodies, cytokines, and nucleic acid-based therapies targeting virus gene expression as well as various types of vaccines. More than 500 patents disclose methodologies of these four biologics with the potential for treating and preventing coronavirus infections, which may be applicable to COVID-19. The information included in this report provides a strong intellectual groundwork for the ongoing development of therapeutic agents and vaccines. 


March 8, 2020


How miRNAs can protect humans from coronaviruses COVID-19, SARS-CoV, and MERS- CoV 


Viral diseases cause significant harm to human health and often cause high mortality. In the past twenty years, humanity has undergone infection by SARS-CoV (severe acute respiratory syndrome), MERS-CoV (Middle East respiratory syndrome) and COVID-19 coronaviruses, which spread from animals to humans and from person to person. These diseases have led to large economic losses. To fight coronaviruses and other viruses, it is proposed to use miRNAs, which regulate protein synthesis at the translational level. MirTarget program was used to determine the following binding characteristics: the locations of miRNA binding sites in the 3'UTR, 5'UTR, and CDS; the free energy interaction ∆G between miRNA and mRNA; the ΔG/ΔGm value, where ΔGm is equal to the free energy binding of miRNA with its full complementary nucleotide sequence; and the nucleotide interaction schemes between miRNAs and mRNAs. Out of 2565 miRNAs, miR-4778-3p, miR- 6864-5p and miR-5197-3p were identified as the most effectively interacting with the gRNA of SARS-CoV, MERS-CoV and COVID-19, respectively. Based on the miR-4778-3p, miR-6864-5p and miR-5197-3p sequences, complete complementary miRNA (cc-miR) binding sites in the gRNA coronaviruses were created. The detected binding sites of these cc-miRs did not form intramolecular complexes in the 2D structure of the gRNA of SARS- CoV, MERS-CoV, and COVID-19 with a value of more than 85%. Therefore, the cc-miRs will bind gRNA at these sites without competition. The cc-miRs for SARS-CoV, MERS-CoV, and COVID-19 did not have target genes among the 17508 human coding genes with a ΔG/ΔGm of more than 85%, which implies the absence of side effects of these cc-miRs on the translation of human mRNAs. cc-miRs can be used as therapeutic agents by incorporating them into exosomes or other vesicles and introducing them into the blood or lung by inhalation. The introduction of cc-miR into the blood will suppress the reproduction of the virus in the blood and in all organs into which it can enter. The proposed method of inhibiting the reproduction of coronaviruses can be used for other viruses. 

March 5, 2020


Activating Organ’s Immunizing Power Against COVID–19–Learning From SARS 


Spike protein is an important component of coronavirus structure and the formation of ACE2 (angiotensin converting enzyme 2)–spike complex mediates virus entry to host cells. C–type lectin family are widely distribute on the surface of human cells and have been shown to activate the immune system. In this article, we first illustrate why we can “learn from SARS” with phylogenetic analysis. Then, we use SARS spike protein structure, to inferring our molecular docking experiment, revealing the potential capacity of C–type lectin to directly interact with spike protein obstructs the formation of spike–ACE2 complex. Considering the expression profile of C–type lectin family changing significantly during infection, we predict certain members of this kind of protein as potential therapeutic target and verify their assumed function by inferring an C–type lectin–dependent CD4/CD28 T cell survival molecular network with endogenous molecular network theory (EMT) and comparing the predicted expression trend corresponding to each molecular with experiment data.

March 4, 2020


Efficacy of Dao Yin in Patients with 2019 Novel Coronavirus Pneumonia: Study Protocol for a Randomized Controlled Trial


The study is a multicenter randomized controlled trial with parallel-group design including two intervention groups: a conventional therapy group and a conventional therapy plus Dao Yin group. A total of 186 eligible participants will be randomly assigned to the groups in a 1:1 ratio. The routine treatment of the two groups is performed daily according to guideline, and Dao Yin is performed once a day until the patient is out of the hospital. The primary outcome is the Length of Hospital Stay (LHS). Secondary outcomes include the vital signs, respiratory symptoms, questionnaire of mental health and the quantity of immune cells. The outcomes will be assessed at five points including the baseline, 3th, 6th, 9th day during hospitalization and the discharge day. The significance level is 5%. This study will focus on the value of a conventional therapy plus Dao Yin as the treatment for 2019-nCoV and will explore any potential connection among the outcomes.

March 4, 2020


Traditional Chinese Medicine for COVID-19 Treatment


The effective cure rate of QPD against COVID-19 is over 90 %. According to the theory of TCM, the target organ location of COVID-19 is the lung, and the etiology attribute is “damp and toxin plague”. The network pharmacology analysis showed that QPD has an overall regulatory effect via multi-component and multi-target. The primary site of pharmacological action is the lung, as 16 herbs to lung meridian, which indicated that the decoction is mainly specific for lung diseases. In addition, it can play the role of dehumidification through the rise and fall of the spleen and stomach, and exhibited the protection for heart, kidney and other organs

February 28, 2020


High-dose Intravenous Vitamin C Treatment for COVID-19


COVID-19 pneumonia seems to be a lung injury caused by the hyperactivation immune effector cells. High-dose vitamin C may result in immunosuppression at the level of these effectors. Therefore, intravenous high-dose vitamin C could be safe and beneficial choice of treatment in the early stages of COVID-19.

February 27, 2020


COVID-19: Combining Antiviral and Anti-Inflammatory Treatments


Baricitinib, fedratinib, and ruxolitinib are potent and selective JAK inhibitors approved for indications such as rheumatoid arthritis and myelofibrosis. All three are powerful anti-inflammatories that, as JAK–STAT signalling inhibitors, are likely to be effective against the consequences of the elevated levels of cytokines (including interferon-γ) typically observed in people with COVID-19·2 Although the three candidates have similar JAK inhibitor potencies, a high affinity for AAK1 suggests baricitinib is the best of the group, especially given its once-daily oral dosing and acceptable side effect profile.

February 27, 2020


Discovery of Potential Drugs for COVID-19 Based on the Connectivity Map


According to the dataset of genes co-expressed with ACE2 in the colonic epithelial cells, we established a protein-protein interaction (PPI) Network and selected

hub genes from them. The cluster analysis was performed to find out the dense region of the PPI Network. Then, gene ontology (GO) and pathway enrichment analysis were performed to explore the main function of genes co-expressed with ACE2. Finally, we predicted the potential drugs for the treatment of COVID-19 based on the connectivity map (Cmap) .

February 26, 2020 


COVID-19 Orf3b Protein: The Putative Biological Function and the Therapeutic Target


The analysis of the COVID-19 Orf3b performed by the informational spectrum methodology suggests that this protein acts as a modulator of the interferon signaling network by binding to Karyopherin proteins. The binding site for Karyopherins on the Orf3 protein (residues 15-29) is proposed as a possible therapeutic target for COVID-19.

February 26, 2020


Identifying COVID-19 Drug-Sites Susceptible To Clinically Safe Zn-ejector Drugs Using Evolutionary/Physical Principles


We proposed that Zn-ejecting agents, FDA-approved or in clinical trials can be used to target the predicted labile Zn-sites: We showed that disulfiram, a cysteine modifier could eject Zn2+ from the predicted labile Zn-Cys4 site in the hepatitis C virus (HCV) NS5A protein, inhibiting viral replication, and that inhibition was enhanced when disulfiram was combined with interferon-a. Subsequently, disulfiram was found to eject Zn2+ and inhibit replication in other viruses, notably MERS-CoV and SARS-CoV PLpro papain-like proteases (PLpro). Based on these findings, our aim is to determine if the Covid-19 virus contains druggable Zn-sites that can be targeted by clinically used Zn-ejectors.

February 22, 2020 


Evaluation of the Efficacy and Safety of Intravenous Remdesivir in Adult Patients with Severe Pneumonia Caused by COVID-19 Virus

Infection: Study Protocol for a Phase 3 Randomized, Double-blind, Placebo-controlled, Multicentre Trial


The clinical manifestations of COVID-19 virus infection include asymptomatic infection, mild upper respiratory symptoms, severe viral pneumonia with respiratory failure and even death. There are no antivirals of proven clinical efficacy in coronavirus infections. Remdesivir (GS-5734), a nucleoside analogue, has inhibitory effects on animal and human highly pathogenic coronaviruses, including highkly pathogenic MERS-CoV and SARS-CoV, in in-vitro and in-vivo experiments. It is also inhibitory against COVID-19 virus in-vitro. The aim of this study is to assess the efficacy and safety of remdesivir in adult patients with severe pneumonia caused by COVID-19 virus infection.

February 19, 2020


Chloroquine Phosphate Has Shown Apparent Efficacy in Treatment of COVID-19 Associated Pneumonia in Clinical Studies


The coronavirus disease 2019 (COVID-19) virus is spreading rapidly, and scientists are endeavoring to discover drugs for its efficacious treatment in China. Chloroquine phosphate, an old drug for treatment of malaria, is shown to have apparent efficacy and acceptable safety against COVID-19 associated pneumonia in multicenter clinical trials conducted in China. The drug is recommended to be included in the next version of the Guidelines for the Prevention, Diagnosis, and Treatment of Pneumonia Caused by COVID-19 issued by the National Health Commission of the People's Republic of China for treatment of COVID-19 infection in larger populations in the future.

February 13, 2020


Traditional Chinese Medicine for Treating Novel Coronavirus (2019-nCoV) Pneumonia: Protocol for a Systematic Review and Meta-Analysis


This systematic review and meta-analysis will assess studies of the effects of TCM in 2019-nCoV-infected pneumonia (NCIP). We will search electronic databases including PubMed, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science and Technology Periodical Database (VIP) and Wanfang database using keywords related to NCIP and TCM. Reference lists of relevant trials and reviews will be searched. We will manually search grey literature, such as conference proceedings and academic degree dissertations, and trial registries. Two independent reviewers will screen studies, extract data and evaluate risk of bias.

February 11, 2020 


Anti-SARS and Anti-HCV Drugs Repurposing Against the Papain-like Protease of the Newly Emerged Coronavirus (2019-nCoV)


The most famous two strains of HCoV are the Severe Acute Respiratory Syndrome coronavirus (SARS CoV) and the Middle East Respiratory Syndrome coronavirus (MERS CoV). The former had emerged in China in 2002 while the latter emerged in the Middle East region in 2012 and South Korea in 2015. In this study, the newly emerged 2019-nCoV papain-like protease (PLpro) is targeted by anti-SARS PLpro drugs and the anti-Hepatitis C Virus (HCV) Non-structural protein 3 (NS3) serine protease drugs. Sequence analysis, modeling, and docking are used to get a valid model for 2019-nCoV PLpro. The results suggest the effectiveness of the anti-SARS drugs (GRL-0667, GRL-0617, and Mycophenolic acid) and the anti-HCV drugs (Grazoprevir, Telaprevir, and Boceprevir) as potent inhibitors against the newly emerged coronavirus.

January 25, 2020


Remdesivir and Chloroquine Effectively Inhibit the Recently Emerged Novel Coronavirus (2019-nCoV) in Vitro


Our findings reveal that remdesivir and chloroquine are highly effective in the control of 2019-nCoV infection in vitro. Since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, we suggest that they should be assessed in human patients suffering from the novel coronavirus disease.