An updated review on potential therapeutic drug candidates, vaccines and an insight on patents filed for COVID-19.
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ABSTRACT:
SUBMITTER: Rao GSNK
PROVIDER: S-EPMC8498785 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThis article is based upon data gathered during a study conducted in partnership with the World Intellectual Property Organization on the patent status of products appearing on the World Health Organization's 2013 Model List of Essential Medicines (MLEM). It is a statistical analysis aimed at answering: in which developing countries are patents on essential medicines being filed?MethodsPatent data were collected by linking those listed in the United States and Canada's medicine patent registers to corresponding patents in developing countries using two international patent databases (INPADOC and Derwent) via a commerical-grade patent search platform (Thomson Innovation). The respective supplier companies were then contacted to correct and verify our data. We next tallied the number of MLEM patents per developing country. Spearman correlations were done to assess bivariate relationships between variables, and a multivariate regression model was developed to explain the number of MLEM patents in each country using SPSS 23.0.ResultsA subset of 20 of the 375 (5%) products on the 2013 MLEM fit our inclusion criteria. The patent estate reports (i.e., the global list of patents for a given drug) varied greatly in their number with a median of 48 patents (interquartile range [IQR]: 26-76). Their geographic reach had a median of 15% of the developing countries sampled (IQR: 8-28%). The number of developing countries covered appeared to increase with the age of the patent estate (r = .433, p = 0.028). The number of MLEM patents per country was significantly positively associated with human development index (HDI), gross domestic income (GDI) per capita, total healthcare expenditure per capita, population size, the Rule of Law Index, and average education level. Population size, GDI per capita, and healthcare expenditure (in % of national expenditure) were predictors of the number of MLEM patents in countries (p = 0.001, p = 0.001, p = 0.009, respectively). Population size was the most important predictor (β = 0.59), followed by income (GDI per capita) (β = 0.32), and healthcare expenditure (β = 0.15). Holding the other factors constant, (i) 14.3 million more people, (ii) $833.33 more per capita (GDI), or (iii) 0.88% more of national spending on healthcare resulted in 1 additional essential medicine patent.ConclusionPopulation was a powerful predictor of the number of patent filings in developing countries along with GDI and healthcare expenditure. The age and historical context of the patent estate may make a difference in the number of patents and countries covered. Broad surveillance and benchmarking of the global medicine patent landscape is valuable for detecting significant shifts that may occur over time. With improved international medicine patent transparency by companies and data available through third parties, such studies will be increasingly feasible.
| S-EPMC5485610 | biostudies-literature
Project description:The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated sixteen of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.
| S-EPMC8020993 | biostudies-literature
Project description:The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to SARS-CoV-2 differential gene expression signatures derived from publicly available data. We utilized three independent published studies to acquire or generate lists of differentially expressed genes between control and SARS-CoV-2-infected samples. Using a rank-based pattern matching strategy based on the Kolmogorov-Smirnov Statistic, the signatures were queried against drug profiles from Connectivity Map (CMap). We validated 16 of our top predicted hits in live SARS-CoV-2 antiviral assays in either Calu-3 or 293T-ACE2 cells. Validation experiments in human cell lines showed that 11 of the 16 compounds tested to date (including clofazimine, haloperidol and others) had measurable antiviral activity against SARS-CoV-2. These initial results are encouraging as we continue to work towards a further analysis of these predicted drugs as potential therapeutics for the treatment of COVID-19.
| S-EPMC8192542 | biostudies-literature
Project description:As of April 15, 2020, the ongoing coronavirus disease 2019 (COVID-2019) pandemic has swept through 213 countries and infected more than 1,870,000 individuals, posing an unprecedented threat to international health and the economy. There is currently no specific treatment available for patients with COVID-19 infection. The lessons learned from past management of respiratory viral infections have provided insights into treating COVID-19. Numerous potential therapies, including supportive intervention, immunomodulatory agents, antiviral therapy, and convalescent plasma transfusion, have been tentatively applied in clinical settings. A number of these therapies have provided substantially curative benefits in treating patients with COVID-19 infection. Furthermore, intensive research and clinical trials are underway to assess the efficacy of existing drugs and identify potential therapeutic targets to develop new drugs for treating COVID-19. Herein, we summarize the current potential therapeutic approaches for diseases related to COVID-19 infection and introduce their mechanisms of action, safety, and effectiveness.
| S-EPMC7175848 | biostudies-literature
Project description:The emergence of highly virulent CoVs (SARS-CoV-2), the etiologic agent of novel ongoing "COVID-19" pandemics has been marked as an alarming case of pneumonia posing a large global healthcare crisis of unprecedented magnitude. Currently, the COVID-19 outbreak has fueled an international demand in the biomedical field for the mitigation of the fast-spreading illness, all through the urgent deployment of safe, effective, and rational therapeutic strategies along with epidemiological control. Confronted with such contagious respiratory distress, the global population has taken significant steps towards a more robust strategy of containment and quarantine to halt the total number of positive cases but such a strategy can only delay the spread. A substantial number of potential vaccine candidates are undergoing multiple clinical trials to combat COVID-19 disease, includes live-attenuated, inactivated, viral-vectored based, sub-unit vaccines, DNA, mRNA, peptide, adjuvant, plant, and nanoparticle-based vaccines. However, there are no licensed anti-COVID-19 drugs/therapies or vaccines that have proven to work as more effective therapeutic candidates in open-label clinical trial studies. To counteract the infection (SARS-CoV-2), many people are under prolonged treatment of many chemical drugs that inhibit the PLpro activity (Ribavirin), viral proteases (Lopinavir/Ritonavir), RdRp activity (Favipiravir, Remdesivir), viral membrane fusion (Umifenovir, Chloroquine phosphate (CQ), Hydroxychloroquine phosphate (HCQ), IL-6 overexpression (Tocilizumab, Siltuximab, Sarilumab). Mesenchymal Stem Cell therapy and Convalescent Plasma Therapy have emerged as a promising therapeutic strategy against SARS-CoV-2 virion. On the other hand, repurposing previously designed antiviral agents with tolerable safety profile and efficacy could be the only promising approach and fast response to the novel virion. In addition, research institutions and corporations have commenced the redesign of the available therapeutic strategy to manage the global crisis. Herein, we present succinct information on selected anti-COVID-19 therapeutic medications repurposed to combat SARS-CoV-2 infection. Finally, this review will provide exhaustive detail on recent prophylactic strategies and ongoing clinical trials to curb this deadly pandemic, outlining the major therapeutic areas for researchers to step in.
| S-EPMC8015872 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19), an acute onset pneumonia caused by a novel Betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in the Wuhan City of China in December 2019 and evolved into a global pandemic. To date, there are no proven drugs or vaccines against this virus. Hence, the situation demands an urgent need to explore all potential therapeutic strategies that can be made available to prevent the disease progression and improve patient outcomes. In absence of clinically proven treatment guidelines, several repurposed drugs and investigational agents are currently being evaluated in clinical trials for their probable benefits in the treatment of COVID-19. These include antivirals (remdesivir, lopinavir/ritonavir, umifenovir, and favipiravir), interferon, antimalarials (chloroquine/hydroxychloroquine), antiparasitic drugs (ivermectin and nitazoxanide), biologics (monoclonal antibodies and interleukin receptor antagonist), cellular therapies (mesenchymal stem cells and natural killer cells), convalescent plasma, and cytokine adsorber. Though several observational studies have claimed many of these agents to be effective based on their in vitro activities and extrapolated evidence from SARS and Middle East respiratory syndrome (MERS) epidemics, the currently available data remains inconclusive because of ill-defined patient selection criteria, small sample size, lack of concurrent controls, and use of intermediary outcomes instead of patient-relevant outcomes. Moreover, there is a need to clearly define the patient populations who warrant therapy and also the timing of initiation of treatment. Understanding the disease pathology responsible for the clinical manifestations of COVID-19 is imperative to identify the potential targets for drug development. This review explains the pathophysiology of COVID-19 and summarizes the potential treatment candidates, which can provide guidance in developing effective therapeutic strategies.
| S-EPMC7527880 | biostudies-literature
Project description:Effective therapies for coronavirus disease 2019 (COVID-19) are urgently needed. Maladaptive hyperinflammation and excessive cytokine release underlie the disease severity, with antiinflammatory and cytokine inhibiting agents expected to exert therapeutic effects. A major present challenge is identification of appropriate phase of the illness for a given intervention to yield optimum outcomes. Considering its established disease biomarker and drug discovery potential, a compendious analysis of existing transcriptomic data is presented here toward addressing this gap. The analysis is based on COVID-19 data related to intensive care unit (ICU) and non-ICU admissions, discharged and deceased patients, ventilation and non-ventilation phases, and high oxygen supplementation. It integrates transcriptomic data related to the effects of, in various cellular treatment models, the COVID-19 randomized clinical trial (RCT) successful drug dexamethasone, and the failed drug, with a potential to harm, hydroxychloroquine/chloroquine. Similarly, effects of various COVID-19 candidate drugs/anticytokines as well as proinflammatory cytokines implicated in the illness are also examined. The underlying assumption was that compared to COVID-19, an effective drug/anticytokine and a disease aggravating agent would affect gene regulation in opposite and same direction, in that order. Remarkably, the assumption was supported with respect to both the RCT drugs. With this control validation, etanercept, followed by tofacitinib and adalimumab, showed transcriptomic effects predictive of benefits in both ventilation and non-ventilation ICU stages as well as in non-ICU phase. On the other hand, canakinumab showed potential for effectiveness in high oxygen supplementation phase. These findings may inform experimental and clinical studies toward drug repurposing in COVID-19.
| S-EPMC8463310 | biostudies-literature
Project description:Introduction: Coronaviruses encode a helicase that is essential for viral replication and represents an excellent antiviral target. However, only a few coronavirus helicase inhibitors have been patented. These patents include drug-like compound SSYA10-001, aryl diketo acids (ADK), and dihydroxychromones. Additionally, adamantane-derived bananins, natural flavonoids, one acrylamide derivative [(E)-3-(furan-2-yl)-N-(4-sulfamoylphenyl)acrylamide], a purine derivative (7-ethyl-8-mercapto-3-methyl-3,7-dihydro-1 H-purine-2,6-dione), and a few bismuth complexes. The IC50 of patented inhibitors ranges between 0.82 μM and 8.95 μM, depending upon the assays used. Considering the urgency of clinical interventions against Coronavirus Disease-19 (COVID-19), it is important to consider developing antiviral portfolios consisting of small molecules.Areas covered: This review examines coronavirus helicases as antiviral targets, and the potential of previously patented and experimental compounds to inhibit the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) helicase.Expert opinion: Small molecule coronavirus helicase inhibitors represent attractive pharmacological modalities for the treatment of coronaviruses such as SARS-CoV and SARS-CoV-2. Rightfully so, the current emphasis is focused upon the development of vaccines. However, vaccines may not work for everyone and broad-based adoption of vaccinations is an increasingly challenging societal endeavor. Therefore, it is important to develop additional pharmacological antivirals against the highly conserved coronavirus helicases to broadly protect against this and subsequent coronavirus epidemics.
| S-EPMC8074651 | biostudies-literature
Project description:Coronaviruses are pleomorphic, enveloped, or spherical viruses, which have a size ranging from 80 to 120 nm. These viruses act on receptors that cause the triggering of fusion. Coronaviruses were first described after cultivation from patients with common colds by Tyrell and Bynoe in 1966. There are various subtypes of coronavirus, 7 out of these can cause infection in human beings. The Alpha subtype is responsible for mild infection showing symptoms or infection without any prevailing symptoms. On the other hand, the beta subtype is responsible for very serious diseases leading to fatality. The lineage of this novel SARS-CoV-2 falls under the beta lineage of the beta coronavirus which has been observed to have a relation to the MERS and SARS coronavirus. In the Huanan market selling seafood, the transition of this novel virus in humans from animals has occurred. It has the potential to be the cause of widespread fatality amongst the people of the globe. On August 16, 2020, the World Health Organisation had reported 2,1294,845 cases which are confirmed to date out of which 413,372 deaths have occurred. Currently, no targeted antiviral vaccines or drugs to fight against COVID-19 infection have been approved for use in humans. This pandemic is fast emerging and drug repurposing is the only ray of hope which can ensure quick availability. Vaccine development is progressing each day with various platforms such as DNA, Live Attenuated Virus, Non-Replicating Viral Vector, Protein Subunit, and RNA, being utilized for the development. COVID-19 attacks the immune system of the host & this can result in a cytokine storm. As a result, various herbal agents both acting as antivirals and immunomodulatory can also be used. Convalescent Plasma Therapy and Mesenchymal Stem Cell therapy are also being explored as a plausible therapeutic. There remains a considerable unmet need for therapeutics to be addressed. The development and availability of accessible and efficient therapy are essential for the treatment of patients. This review discusses the epidemiology, pathogenesis, the tale of origin, and transmission of COVID-19 or Sars-Cov2 virus and gives evidence of potential therapeutic agents that can be explored to cast away this pandemic.
| S-EPMC7550915 | biostudies-literature
Project description:Coronavirus disease 2019 (COVID-19) is an unprecedented disease caused by highly pathogenic SARS-CoV-2 and characterized by extreme respiratory deterrence, pneumonia and immune damage. The phylogenetic analysis demonstrated the sequence similarity of SARS-CoV-2 with other SARS-like bat viruses. The primary source and intermediate host are not yet confirmed, although transmission from human to human is universally confirmed. The new SARS-CoV-2 virus reaches cells via ACE-2 and subsequently down-regulates ACE-2, leaving angiotensin II unbalanced in affected organs primarily in the lungs, heart, brain, and kidneys. As reported recently, numerous secondary complications i.e., neurological, nephrological, cardiovascular, gastrointestinal, immune, and hepatic complications, are associated with COVID-19 infection along with prominent respiratory disease including pneumonia. Extensive research work on recently discovered SARS-CoV-2 is in the pipeline to clarify pathogenic mechanisms, epidemiological features, and identify new drug targets that will lead to the development of successful strategies for prevention and treatment. There are currently no appropriate scientifically approved vaccines/drugs for COVID-19. Nonetheless, few broad-spectrum antiviral drugs, azithromycin were tested against COVID-19 in clinical trials, and finally, FDA approved emergency use of remdesivir in hospitalized COVID-19 patients. Additionally, administration of convalescent plasma obtained from recovered COVID-19 patients to infected COVID-19 patients reduces the viral burden via immunomodulation. This review analysis therefore concentrates primarily on recent discoveries related to COVID-19 pathogenesis along with a full description of the structure, genome, and secondary complication associated with SARS-CoV-2. Finally, a short and brief clinical update has been provided concerning the development of therapeutic medications and vaccines to counter COVID-19.
| S-EPMC7366108 | biostudies-literature