Repurposed GI Drugs in the Treatment of COVID-19.
Ontology highlight
ABSTRACT:
SUBMITTER: Aguila EJT
PROVIDER: S-EPMC7324004 | biostudies-literature | 2020 Aug
REPOSITORIES: biostudies-literature
Publications
Repurposed GI Drugs in the Treatment of COVID-19.
Aguila Enrik John T EJT Cua Ian Homer Y IHY
Digestive diseases and sciences 20200629 8
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Project description:The COVID-19 pandemic caused by SARS-CoV-2 has placed severe constraints on healthcare systems around the globe. The SARS-CoV-2 virus has caused upheaval in the healthcare and economic sectors worldwide. On the 20th of May 2020, the World Health Organisation declared COVID-19 a global pandemic due to the unprecedented number of cases reported around the globe. As of the 4th of November 2022, there were 637,117,429 coronavirus cases reported globally by Worldometer stats, with 6,602,572 related deaths. In South Africa, there were approximately 4,029,496 coronavirus cases and 102,311 associated deaths. As such, there is a need for efficacious therapeutic regimes. There has been a paucity of knowledge encompassing the use of effective and specific antiviral drug therapies for treating COVID-19 since the outbreak. In this review, we provide valuable insights into the repurposing of current drugs for COVID-19. Drug repurposing provides a suitable option for the discovery of efficacious drugs for COVID-19, thereby decreasing the costs and turnaround times of drug development strategies. This review provides an overview of ten drugs, including antimalarial, antiparasitic, anti-inflammatory, nucleoside analogue, monoclonal-antibody drugs, that were repurposed for the potential treatment of COVID-19.
| S-EPMC9774286 | biostudies-literature
Project description:The global outbreak of COVID-19 viral infection is associated with the absence of specific drug(s) for fighting this viral infection. About 10 million people are already infected, about 500 000 deaths all over the world to date. Great efforts have been made to find solutions for this viral infection, either vaccines, monoclonal antibodies, or small molecule drugs; this can stop the spread of infection to avoid the expected human, economic and social catastrophe associated with this infection. In the literature and during clinical trials in hospitals, several FDA approved drugs for different diseases have the potential to treat or reduce the severity of COVID-19. Repurposing of these drugs as potential agents to treat COVID-19 reduces the time and cost to find effective COVID-19 agents. This review article summarizes the present situation of transmission, pathogenesis and statistics of COVID-19 in the world. Moreover, it includes chemistry, mechanism of action at the molecular level of the possible drug molecules which are liable for redirection as potential COVID-19 therapeutic agents. This includes polymerase inhibitors, protease inhibitors, malaria drugs, lipid lowering statins, rheumatoid arthritis drugs and some miscellaneous agents. We offer research data and knowledge about the chemistry and biology of potential COVID-19 drugs for the research community in this field.
| S-EPMC9055522 | biostudies-literature
Project description:The pandemic of the coronavirus disease 2019 (COVID-19) represents an unprecedented challenge to identify effective drugs for prevention and treatment. While the world's attention is focused on news of COVID-19 vaccine updates, clinical management still requires improvement. Due to the similarity of cancer-induced inflammation, immune dysfunction, and coagulopathy to COVID-19, anticancer drugs, such as Interferon, Pembrolizumab or Bicalutamide, are already being tested in clinical trials for repurposing, alone or in combination. Given the rapid pace of scientific discovery and clinical data generated by the large number of people rapidly infected, clinicians need effective medical treatments for this infection.
| S-EPMC8229933 | biostudies-literature
Project description:Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began churning out incredulous terror in December 2019. Within several months from its first detection in Wuhan, SARS-CoV-2 spread to the rest of the world through droplet infection, making it a pandemic situation and a healthcare emergency across the globe. The available treatment of COVID-19 was only symptomatic as the disease was new and no approved drug or vaccine was available. Another challenge with COVID-19 was the continuous mutation of the SARS-CoV-2 virus. Some repurposed drugs, such as hydroxychloroquine, chloroquine, and remdesivir, received emergency use authorization in various countries, but their clinical use is compromised with either severe and fatal adverse effects or nonavailability of sufficient clinical data. Molnupiravir was the first molecule approved for the treatment of COVID-19, followed by Paxlovid™, monoclonal antibodies (MAbs), and others. New molecules have variable therapeutic efficacy against different variants or strains of SARS-CoV-2, which require further investigations. The aim of this review is to provide in-depth information on new molecules and repurposed drugs with emphasis on their general description, mechanism of action (MOA), correlates of protection, dose and dosage form, route of administration, clinical trials, regulatory approval, and marketing authorizations.
| S-EPMC9967525 | biostudies-literature
Project description:The SARS-CoV-2 virus needs multiple copies for its multiplication using an enzyme RNA-dependent RNA polymerase (RdRp). Remdesivir inhibits viral RdRp, controls the multiplication of the virus, and protects patients. However, treatment of COVID-19 with remdesivir involves adverse effects. Many ongoing clinical trials are exploring the potential of the combination of remdesivir with repurposed drugs by targeting multiple targets of virus and host human simultaneously. Better results were obtained with the remdesivir-baricitinib combination treatment for COVID-19 compared to the treatment with remdesivir alone. Notably, recovery from COVID-19 was found to be 8 days less via the remdesivir-baricitinib combination treatment as compared to remdesivir treatment alone. Furthermore, the mortality rate via the remdesivir-baricitinib combination treatment was lower compared to the remdesivir-only treatment. Remdesivir targets the SARS-CoV-2 enzyme while baricitinib targets the host human enzyme. Simultaneously, remdesivir and baricitinib as a combination inhibit their target viral RdRp and human Janus kinase, respectively. Ongoing trials for the combination of drugs will suggest in the future whether they may reduce the recovery time, reduce the mortality rate, and improve patient clinical status for noninvasive ventilation. In the future, simultaneously targeting virus replication enzymes and host human kinases may be the strategy for SARS-CoV-2 therapeutics.
| S-EPMC9134007 | biostudies-literature
Project description:The COVID-19 pandemic has caused millions of deaths and massive societal distress worldwide. Therapeutic solutions are urgently needed but de novo drug development remains a lengthy process. One promising alternative is computational drug repurposing, which enables the prioritization of existing compounds through fast in silico analyses. Recent efforts based on molecular docking, machine learning, and network analysis have produced actionable predictions. Some predicted drugs, targeting viral proteins and pathological host pathways are undergoing clinical trials. Here, we review this work, highlight drugs with high predicted efficacy and classify their mechanisms of action. We discuss the strengths and limitations of the published methodologies and outline possible future directions. Finally, we curate a list of COVID-19 data portals and other repositories that could be used to accelerate future research.
| S-EPMC8323501 | biostudies-literature
Project description:Background: Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Methods: Inhibition of angiotensin-converting enzyme 2 (ACE2) caused by the spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We performed drug repositioning analysis to identify drug candidates that reverse gene expression pattern in L1000 lung cell line HCC515 treated with ACE2 inhibitor. We confirmed these drug candidates by similar bioinformatics analysis using lung tissues from patients deceased from COVID-19. We further investigated deregulated genes and pathways related to lung injury, as well as the gene-pathway-drug candidate relationships. Results: We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19. Further bioinformatics analysis shows that 12 significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues. These include signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and chemokine signaling pathways. All 12 pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares 11 of 12 pathways with COL-3 and common target genes such as RHOA. It also uniquely targets other genes related to lung injury, such as CALR and MMP14. Conclusions: This study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have potential as repurposed drugs for its treatment.
| S-EPMC7468567 | biostudies-literature
Project description:BackgroundWorld Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).MethodsWe randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.ResultsAt 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.ConclusionsThese remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).
| S-EPMC7727327 | biostudies-literature
Project description:Coronavirus disease (COVID-19) is an infectious disease discovered in 2019 and currently in outbreak across the world. Lung injury with severe respiratory failure is the leading cause of death in COVID-19, brought by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2). However, there still lacks efficient treatment for COVID-19 induced lung injury and acute respiratory failure. Inhibition of Angiotensin-converting enzyme 2 (ACE2) caused by spike protein of SARS-CoV-2 is the most plausible mechanism of lung injury in COVID-19. We propose two candidate drugs, COL-3 (a chemically modified tetracycline) and CGP-60474 (a cyclin-dependent kinase inhibitor), for treating lung injuries in COVID-19, based on their abilities to reverse the gene expression patterns in HCC515 cells treated with ACE2 inhibitor and in human COVID-19 patient lung tissues. Further bioinformatics analysis shows that twelve significantly enriched pathways (P-value <0.05) overlap between HCC515 cells treated with ACE2 inhibitor and human COVID-19 patient lung tissues, including signaling pathways known to be associated with lung injury such as TNF signaling, MAPK signaling and Chemokine signaling pathways. All these twelve pathways are targeted in COL-3 treated HCC515 cells, in which genes such as RHOA, RAC2, FAS, CDC42 have reduced expression. CGP-60474 shares eleven of twelve pathways with COL-3 with common target genes such as RHOA. It also uniquely targets genes related to lung injury, such as CALR and MMP14. In summary, this study shows that ACE2 inhibition is likely part of the mechanisms leading to lung injury in COVID-19, and that compounds such as COL-3 and CGP-60474 have the potential as repurposed drugs for its treatment.
| S-EPMC7280878 | biostudies-literature
Project description:The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug's toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.
| S-EPMC8325362 | biostudies-literature