Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database.
TL;DR: Zhang et al. as discussed by the authors used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19 and identified genes coexpressed with ACE2 in healthy lung samples and analyzed the significant genes.
Abstract: Background The coronavirus disease 2019 (COVID-19) has become a worldwide public health crisis. At present, there are no effective antiviral drugs to treat COVID-19. Although some vaccines have been developed, late-stage clinical trials that allow licensure by regulatory agencies are still needed. Previous reports have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV are highly homologous and both use angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells, and SARS-CoV infection reduces the ACE2 expression in the lung. Therefore, the analysis of genes co-expressed with ACE2 in the lung may uncover the underlying mechanism of COVID-19. Finally, we used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19. Method Based on the differentially expressed genes (DEGs), indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid (BALF) cells of patients with COVID-19, we performed functional enrichment analysis and hub gene cluster analysis. Furthermore, we identified genes co-expressed with ACE2 in healthy lung samples and analyzed the significant genes. Additionally, to identify several candidate drugs for the treatment of COVID-19, we queried Cmap using DEGs and genes co-expressed with ACE2. Results and conclusion The up-regulated genes in the BALF cells of patients with COVID-19 are related to viral mRNA translation. The down-regulated genes are related to immune response functions. Genes positively correlated with ACE2 are related to immune defense and those negatively correlated are enriched in synaptic transmission functions. The results reflected prosperous viral proliferation and immune dysfunction in patients. Furthermore, ACE2 may not only mediate viral entrance, but also play an important role in immune defense. By using Cmap with transcriptome profiles of patients with COVID-19, we identified candidate drugs for the treatment of COVID-19, such as amantadine and acyclovir.
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TL;DR: In this paper , two machine learning approaches for drug repurposing are presented for SARS-CoV-2 infection/replication in COVID-19 patients, one based on matrix factorization and the other based on network medicine.
17 citations
DOI•
09 Nov 2021
TL;DR: In this article, two machine learning approaches for drug repurposing are presented for SARS-CoV-2 infection/replication in COVID-19 patients, one based on matrix factorization and the other based on network medicine.
Abstract: We present two machine learning approaches for drug repurposing. While we have developed them for COVID-19, they are disease-agnostic. The two methodologies are complementary, targeting SARS-CoV-2 and host factors, respectively. Our first approach consists of a matrix factorisation algorithm to rank broad-spectrum antivirals. Our second approach, based on network medicine, uses graph kernels to rank drugs according to the perturbation they induce on a subnetwork of the human interactome that is crucial for SARS-CoV-2 infection/replication. Our experiments show that our top predicted broad-spectrum antivirals include drugs indicated for compassionate use in COVID-19 patients; and that the ranking obtained by our kernel-based approach aligns with experimental data. Finally, we present the COVID-19 Repositioning Explorer (CoREx), an interactive online tool to explore the interplay between drugs and SARS-CoV-2 host proteins in the context of biological networks, protein function, drug clinical use, and Connectivity Map. CoREx is freely available at: https://paccanarolab.org/corex/.
17 citations
TL;DR: In this article, state-of-the-art X-ray co-crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) were analyzed with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.
Abstract: Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti-SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti-SARS-CoV-2 drugs.
15 citations
TL;DR: Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadines has been entertained as mentioned in this paper.
Abstract: Several adamantanes have established actions against coronaviruses. Amantadine, rimantadine, bananins and the structurally related memantine are effective against human respiratory coronavirus HCoV-OC43, bovine coronavirus and severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and a spiroadamantane amine is effective against the coronavirus strain 229E. Molecular docking studies suggest that amantadine may block the viral E protein channel, leading to impaired viral propagation. Additionally, amantadine analogues may inhibit entry of the virus into the host cell by increasing the pH of the endosomes and thus inhibiting the action of host cell proteases such as Cathepsin L. High-throughput drug screen gene expression analysis identified compounds able to down-regulate Cathepsin L expression where the fifth most potent agent of 466 candidates was amantadine. Amantadine inhibits severe acute respiratory syndrome coronavirus 2 replication in vitro but does not inhibit the binding of the spike protein to ACE2. Adamantanes also may act against coronaviruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) via antagonism of glutamate (NMDA) and the α-7 subtype of the nicotinic acetylcholine receptor located on bronchial and alveolar epithelial cells. As an NMDA receptor antagonist, memantine has the potential to inhibit entry of SARS-CoV-2 into these cell populations. Amantadine and memantine are widely employed for the treatment of neurodegenerative diseases and a pathophysiologic link between the antiviral and anti-Parkinson actions of amantadine has been entertained. Case reports involving 23 patients with reverse transcription polymerase chain reaction-confirmed coronavirus disease 2019 (COVID-19) and a range of co-morbidities including type 2 diabetes mellitus, Parkinson's disease, multiple sclerosis and severe cognitive impairment reveal significant potential benefits of amantadine and memantine for the prevention and/or treatment of coronavirus disease 2019 and its neurological complications.
13 citations
TL;DR: In this article, the authors evaluated all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics, and found that antivirus therapy increased mortality risk.
Abstract: The aim of our study was to evaluate all-cause mortality risk in patients with laboratory-confirmed COVID-19 in Mexico City treated with repurposed antivirals and antibiotics. This real-world retrospective cohort study contemplated 395,343 patients evaluated for suspected COVID-19 between February 24 and September 14, 2020 in 688 primary-to-tertiary medical units in Mexico City. Patients were included with a positive RT-PCR for SARS-CoV-2; those receiving unspecified antivirals, excluded; and groups of antivirals prescribed in 2 days) use of antivirals on mortality in a sub-cohort of patients. Multivariable adjustment, propensity score matching, generalized estimating equations, and calculation of E-values were performed to limit confounding. 136,855 patients were analyzed; mean age 44.2 (SD:16.8) years; 51.3 % were men. 16.6 % received antivirals (3 %), antibiotics (10 %), or both (3.6 %). Antivirals studied were Oseltamivir (n=8414), Amantadine (n=319), Lopinavir-Ritonavir (n=100), Rimantadine (n=61), Zanamivir (n=39), and Acyclovir (n=36). Survival with antivirals (73.7 %, p<0.0001) and antibiotics (85.8 %, p<0.0001) was lower than no antiviral/antibiotic (93.6 %). After multivariable adjustment, increased risk of death occurred with antivirals (HR=1.72, 95 % CI: 1.61-1.84) in ambulatory (HR=4.7, 95 % CI: 3.94-5.62) and non-critical (HR=2.03, 95 % CI: 1.86-2.21) patients. Oseltamivir increased mortality risk in the general population (HR=1.72, 95 % CI: 1.61-1.84), ambulatory (HR=4.79, 95 % CI: 4.01-5.75), non-critical (HR=2.05, 95 % CI: 1.88-2.23), and pregnancy (HR=8.35, 95 % CI: 1.77-39.30); as well as hospitalized (HR=1.13, 95 % CI: 1.01-1.26) and critical patients (HR=1.22, 95 % CI: 1.05-1.43) after propensity score-matching. Early versus late oseltamivir did not modify the risk. Antibiotics were a risk factor in general population (HR=1.13, 95 % CI: 1.08-1.19) and pediatrics (HR=4.22, 95 % CI: 2.01-8.86), but a protective factor in hospitalized (HR=0.81, 95 % CI: 0.77-0.86) and critical patients (HR=0.67, 95 % CI: 0.63-0.72). No significant benefit for repurposed antivirals was observed; oseltamivir was associated with increased mortality. Antibiotics increased mortality risk in the general population but may increase survival in hospitalized and critical patients.
10 citations
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TL;DR: The epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of patients with laboratory-confirmed 2019-nCoV infection in Wuhan, China, were reported.
36,578 citations
"Underlying Mechanisms and Candidate..." refers background in this paper
...Severe and lethal cases also showed organ dysfunction, including shock, acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, liver dysfunction and secondary inflammation (Chen et al., 2020; Huang et al., 2020; Wang et al., 2020; Wei-jie Guan, 2020)....
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TL;DR: The epidemiological and clinical characteristics of novel coronavirus (2019-nCoV)-infected pneumonia in Wuhan, China, and hospital-associated transmission as the presumed mechanism of infection for affected health professionals and hospitalized patients are described.
Abstract: Importance In December 2019, novel coronavirus (2019-nCoV)–infected pneumonia (NCIP) occurred in Wuhan, China. The number of cases has increased rapidly but information on the clinical characteristics of affected patients is limited. Objective To describe the epidemiological and clinical characteristics of NCIP. Design, Setting, and Participants Retrospective, single-center case series of the 138 consecutive hospitalized patients with confirmed NCIP at Zhongnan Hospital of Wuhan University in Wuhan, China, from January 1 to January 28, 2020; final date of follow-up was February 3, 2020. Exposures Documented NCIP. Main Outcomes and Measures Epidemiological, demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Outcomes of critically ill patients and noncritically ill patients were compared. Presumed hospital-related transmission was suspected if a cluster of health professionals or hospitalized patients in the same wards became infected and a possible source of infection could be tracked. Results Of 138 hospitalized patients with NCIP, the median age was 56 years (interquartile range, 42-68; range, 22-92 years) and 75 (54.3%) were men. Hospital-associated transmission was suspected as the presumed mechanism of infection for affected health professionals (40 [29%]) and hospitalized patients (17 [12.3%]). Common symptoms included fever (136 [98.6%]), fatigue (96 [69.6%]), and dry cough (82 [59.4%]). Lymphopenia (lymphocyte count, 0.8 × 109/L [interquartile range {IQR}, 0.6-1.1]) occurred in 97 patients (70.3%), prolonged prothrombin time (13.0 seconds [IQR, 12.3-13.7]) in 80 patients (58%), and elevated lactate dehydrogenase (261 U/L [IQR, 182-403]) in 55 patients (39.9%). Chest computed tomographic scans showed bilateral patchy shadows or ground glass opacity in the lungs of all patients. Most patients received antiviral therapy (oseltamivir, 124 [89.9%]), and many received antibacterial therapy (moxifloxacin, 89 [64.4%]; ceftriaxone, 34 [24.6%]; azithromycin, 25 [18.1%]) and glucocorticoid therapy (62 [44.9%]). Thirty-six patients (26.1%) were transferred to the intensive care unit (ICU) because of complications, including acute respiratory distress syndrome (22 [61.1%]), arrhythmia (16 [44.4%]), and shock (11 [30.6%]). The median time from first symptom to dyspnea was 5.0 days, to hospital admission was 7.0 days, and to ARDS was 8.0 days. Patients treated in the ICU (n = 36), compared with patients not treated in the ICU (n = 102), were older (median age, 66 years vs 51 years), were more likely to have underlying comorbidities (26 [72.2%] vs 38 [37.3%]), and were more likely to have dyspnea (23 [63.9%] vs 20 [19.6%]), and anorexia (24 [66.7%] vs 31 [30.4%]). Of the 36 cases in the ICU, 4 (11.1%) received high-flow oxygen therapy, 15 (41.7%) received noninvasive ventilation, and 17 (47.2%) received invasive ventilation (4 were switched to extracorporeal membrane oxygenation). As of February 3, 47 patients (34.1%) were discharged and 6 died (overall mortality, 4.3%), but the remaining patients are still hospitalized. Among those discharged alive (n = 47), the median hospital stay was 10 days (IQR, 7.0-14.0). Conclusions and Relevance In this single-center case series of 138 hospitalized patients with confirmed NCIP in Wuhan, China, presumed hospital-related transmission of 2019-nCoV was suspected in 41% of patients, 26% of patients received ICU care, and mortality was 4.3%.
16,635 citations
"Underlying Mechanisms and Candidate..." refers background in this paper
...…the corresponding perturbation conforms to the expression of the query signature; n: number of repetitive samples; p-value: The probability of the enrichment of a set of instances in the total set of instances by chance upon execution of a query. inflammation and apoptosis (Jun Wang et al., 2020)....
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...Severe and lethal cases also showed organ dysfunction, including shock, acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, liver dysfunction and secondary inflammation (Chen et al., 2020; Huang et al., 2020; Wang et al., 2020; Wei-jie Guan, 2020)....
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TL;DR: Characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia, and further investigation is needed to explore the applicability of the Mu LBSTA scores in predicting the risk of mortality in 2019-nCoV infection.
16,282 citations
TL;DR: O surto do novo coronavÃrus (COVID-19) em Wuhan, China, iniciado em dezembro de 2019, evoluiu para se tornar uma pandemia global A.
6,850 citations
TL;DR: A biologist-oriented portal that provides a gene list annotation, enrichment and interactome resource and enables integrated analysis of multi-OMICs datasets, Metascape is an effective and efficient tool for experimental biologists to comprehensively analyze and interpret OMICs-based studies in the big data era.
Abstract: A critical component in the interpretation of systems-level studies is the inference of enriched biological pathways and protein complexes contained within OMICs datasets Successful analysis requires the integration of a broad set of current biological databases and the application of a robust analytical pipeline to produce readily interpretable results Metascape is a web-based portal designed to provide a comprehensive gene list annotation and analysis resource for experimental biologists In terms of design features, Metascape combines functional enrichment, interactome analysis, gene annotation, and membership search to leverage over 40 independent knowledgebases within one integrated portal Additionally, it facilitates comparative analyses of datasets across multiple independent and orthogonal experiments Metascape provides a significantly simplified user experience through a one-click Express Analysis interface to generate interpretable outputs Taken together, Metascape is an effective and efficient tool for experimental biologists to comprehensively analyze and interpret OMICs-based studies in the big data era
6,282 citations