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(searched for: doi:10.3389/fimmu.2021.635371)
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Published: 16 February 2022
Frontiers in Microbiology, Volume 13; https://doi.org/10.3389/fmicb.2022.843587

Abstract:
Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in 2019, more than 270 million infections have been reported, and the death toll from the associated coronavirus disease 2019 (COVID-19) has reached 5.5 million. The magnitude of this pandemic has encouraged the repurposing of numerous drugs, with the aim of rapidly curbing the morbidity, mortality, and spread of this new disease. However, this approach has had limited success. Only vaccine development and the repurposing of dexamethasone have impacted COVID-19 severity. Drug repurposing is, perhaps, an effective strategy for identifying antivirals, but there are no shortcuts for drug development. The identification of effective drugs, regardless of previous approval, requires time and funding to confirm and understand the drug target, the drug's toxicity, and its proper use. The lessons learned with COVID-19 should provide a roadmap for approaching drug discovery, when confronting SARS-CoV-2 and other current and future viral threats. From the beginning of the SARS-CoV-2 pandemic in China, it was clear that severe COVID-19 was an inflammatory acute respiratory distress syndrome (ARDS). Indeed, early in the pandemic, COVID-19 progression from mild to moderate to severe was associated with immune dysfunction, hyper-inflammatory response, and sepsis (Zhou et al., 2020). Later studies showed that some patients infected with SARS-CoV-2 developed severe pneumonia and ARDS (Grant et al., 2021). Consequently, both antiviral and immunomodulatory drugs were contemplated and administered early in the pandemic (Martinez, 2020; Cross et al., 2021). Early studies (Tay et al., 2020) searched for parallelisms between SARS-CoV-2-related pneumonia and pneumonias connected to other human coronavirus diseases, such as severe acute respiratory syndrome (SARS-CoV) and Middle East respiratory syndrome (MERS-CoV). However, the pathobiology of SARS-CoV-2-related pneumonia seems to be distinct from pneumonia caused by other respiratory viral and bacterial pathogens; the SARS-CoV-2-related pneumonia displays unusual clinical features and has a longer clinical course than severe pneumonia (Gattinoni et al., 2020; Grant et al., 2021). An accurate clinical characterization of SARS-CoV-2 infections, based on known clinical syndromes, is critical for the identification of effective therapies (Cross et al., 2021). Understandably, early in the SARS-CoV-2 pandemic, several repurposed drugs were quickly translated to the clinic. However, over the 2 last years, the results have been rather poor (Edwards, 2020; Edwards and Hartung, 2021; Martinez, 2021). The repurposed drugs for combating COVID-19 were selected either without a hypothetical basis or with mechanistic hypothetical approaches. Unfortunately, when those candidates were tested in clinical studies, none proved effective against SARS-CoV-2. Given that the repurposed drugs were optimized for a different target, dosage, or tissue, their pharmacology was probably not appropriate for the new indication (Edwards, 2020; Dahlin et al., 2021). In addition, the cellular assays designed for repurposing antivirals, including phenotypic and high-throughput screening assays, are frequently subject to interfering or undesirable bioactive mechanisms (Dahlin et al., 2021). Remarkably, most of the repurposed drugs tested during this pandemic were administered off-label and outside of properly designed observational or clinical trials. However, unsuccessful approaches might reduce the public trust in evidence-based medicine (Cross et al., 2021). Therefore, clinical trials and methodologies for identifying effective drugs should be designed based on methodologies with the highest likelihood of success. Antiviral drugs target key processes in the virus life cycle. These processes include virus cell entry, genome replication, translation, protein processing, and virus particle generation. More than two-thirds of all antivirals approved for human use target viral enzymes, such as viral RNA/DNA polymerases and viral proteases (De Clercq and Li, 2016; Tompa et al., 2021). Importantly, in the last 30 years, no antiviral drug has been approved in the absence of a specific viral target. Thus, perhaps the main drawback of the repurposed antiviral drugs that have been tested unsuccessfully against SARS-CoV-2 has been the absence of an evident mechanism of action (Table 1). Table 1. Most relevant repurposed antiviral drugs against SARS-CoV-2. Hits from antiviral screening based on biochemical or cell-culture assays must be treated with skepticism. Chloroquine and hydroxychloroquine represent a clear example of misinterpreted cell culture results. The efficacy of chloroquine and hydroxychloroquine against SARS-CoV-2 in tissue cultures was determined with African green monkey kidney-derived Vero cells. However, when Vero cells were engineered to express TMPRSS2, a cellular protease that activates SARS-CoV-2 for entry into lung cells, the genetic manipulation rendered SARS-CoV-2–infected Vero cells insensitive to chloroquine (Hoffmann et al., 2020). Accordingly, chloroquine could not block SARS-CoV-2 infections in TMPRSS2-expressing human lung Calu-3 cells; thus, chloroquine targets a viral activation pathway that is not present in human lung cells. Therefore, the drug is unlikely to protect against the spread of SARS-CoV-2. Another example of a misinterpretation of cell culture results was recently reported (Tummino et al., 2021) in a study that demonstrated that phospholipidosis was a shared mechanism underlying the antiviral activity of many repurposed drugs for SARS-CoV-2 (Tummino et al., 2021). Conversely, drugs that were active against the same targets, but did not induce phospholipidosis, were not effective against viruses. Those results strongly suggested that a failure to induce phospholipidosis could explain why most drugs that were selected for repurposing to date lacked...
, A. Ciullo, C. Li, G. Garcia, K. Peck, K. Miyamoto, V. Arumugaswami, E. Marbán
Published: 13 February 2022
Biomaterials and Biosystems, Volume 6; https://doi.org/10.1016/j.bbiosy.2022.100042

The publisher has not yet granted permission to display this abstract.
Debdoot Basu, Vivek P. Chavda,
Current Research in Pharmacology and Drug Discovery, Volume 3; https://doi.org/10.1016/j.crphar.2022.100086

The publisher has not yet granted permission to display this abstract.
Porkodi Ayyar, Umamaheswari Subramanian
Published: 5 January 2022
Pharmacia, Volume 69, pp 51-59; https://doi.org/10.3897/pharmacia.69.e72548

Abstract:
Drug repurposing refers to finding new indications for existing drugs. The paradigm shift from traditional drug discovery to drug repurposing is driven by the fact that new drug pipelines are getting dried up because of mounting Research & Development (R&D) costs, long timeline for new drug development, low success rate for new molecular entities, regulatory hurdles coupled with revenue loss from patent expiry and competition from generics. Anaemic drug pipelines along with increasing demand for newer effective, cheaper, safer drugs and unmet medical needs call for new strategies of drug discovery and, drug repurposing seems to be a promising avenue for such endeavours. Drug repurposing strategies have progressed over years from simple serendipitous observations to more complex computational methods in parallel with our ever-growing knowledge on drugs, diseases, protein targets and signalling pathways but still the knowledge is far from complete. Repurposed drugs too have to face many obstacles, although lesser than new drugs, before being successful.
Published: 4 January 2022
by MDPI
Abstract:
When developing drugs against SARS-CoV-2, it is important to consider the characteristics of patients with different co-morbidities. People infected with HIV-1 are a particularly vulnerable group, as they may be at a higher risk than the general population of contracting COVID-19 with clinical complications. For such patients, drugs with a broad spectrum of antiviral activity are of paramount importance. Glycyrrhizinic acid (Glyc) and its derivatives are promising biologically active compounds for the development of such broad-spectrum antiviral agents. In this work, derivatives of Glyc obtained by acylation with nicotinic acid were investigated. The resulting preparation, Glycyvir, is a multi-component mixture containing mainly mono-, di-, tri- and tetranicotinates. The composition of Glycyvir was characterized by HPLC-MS/MS and its toxicity assessed in cell culture. Antiviral activity against three strains of SARS-CoV-2 was tested in vitro on Vero E6 cells by MTT assay. Glycyvir was shown to inhibit SARS-CoV-2 replication in vitro (IC502–8 μM) with an antiviral activity comparable to the control drug Remdesivir. In addition, Glycyvir exhibited marked inhibitory activity against HIV pseudoviruses of subtypes B, A6 and the recombinant form CRF63_02A (IC50 range 3.9–27.5 µM). The time-dependence of Glycyvir inhibitory activity on HIV pseudovirus infection of TZM-bl cells suggested that the compound interfered with virus entry into the target cell. Glycyvir is a promising candidate as an agent with low toxicity and a broad spectrum of antiviral action.
Zijun Wang, Hui Liu, Yang Li, Xufei Luo, Nan Yang, Meng Lv, Qi Zhou, Qinyuan Li, Ling Wang, Junxian Zhao, et al.
Published: 13 December 2021
Journal of Clinical Epidemiology, Volume 144, pp 163-172; https://doi.org/10.1016/j.jclinepi.2021.12.015

The publisher has not yet granted permission to display this abstract.
Published: 23 November 2021
Abstract:
Introduction: Despite an increasing number of studies, there is as yet no efficient antiviral treatment developed for the disease. In this clinical trial, we examined the efficacy of a novel herbal antiviral preparation comprising Zataria multiflora Boiss, Glycyrrhiza glabra, Cinnamomum Vermont, Allium sativuml, and Syzygium aromaticum in critically ill patients with COVID-19 patients.Methods: A total number of 120 ICU-admitted patients requiring pulmonary support with a diagnosis of COVID-19 pneumonia were recruited to the trial. Participants were equally randomized to receive either the novel antiviral preparation sublingually, for up to two consecutive weeks or till discharge, or normal saline as the matching placebo. Clinical and laboratory parameters as well as survival rates were compared between the two groups at the study end.Results: The cumulative incidence of death throughout the study period was 8.33% in the medication group and 60% in the placebo group (risk ratio: 0.14; 95% confidence interval [CI], 0.05 to 0.32; P<0.001). Survival rates were significantly higher in the treatment group. Additionally, on day 7, several laboratory factors including white blood cells (WBCs) count, C-reactive protein (CRP), and SpO2 were improved in patients treated with the novel antiviral preparation compared with the placebo group.Conclusion: The novel antiviral preparation tested in this trial significantly improved the survival rate and reduced mortality in critically ill patients with COVID-19. Thus, this preparation might be suggested as a potentially promising COVID-19 treatment.Funded by Shimi Teb Salamat Co., Shiraz, Iran, and registered on the Iranian registry of clinical trials (registration No. IRCT20200509047373N2).
, Robert E. McCullumsmith,
Published: 16 November 2021
Translational Psychiatry, Volume 11, pp 1-8; https://doi.org/10.1038/s41398-021-01724-w

Abstract:
Drug repurposing is an invaluable strategy to identify new uses for existing drug therapies that overcome many of the time and financial costs associated with novel drug development. The COVID-19 pandemic has driven an unprecedented surge in the development and use of bioinformatic tools to identify candidate repurposable drugs. Using COVID-19 as a case study, we discuss examples of machine-learning and signature-based approaches that have been adapted to rapidly identify candidate drugs. The Library of Integrated Network-based Signatures (LINCS) and Connectivity Map (CMap) are commonly used repositories and have the advantage of being amenable to use by scientists with limited bioinformatic training. Next, we discuss how these recent advances in bioinformatic drug repurposing approaches might be adapted to identify repurposable drugs for CNS disorders. As the development of novel therapies that successfully target the cause of neuropsychiatric and neurological disorders has stalled, there is a pressing need for innovative strategies to treat these complex brain disorders. Bioinformatic approaches to identify repurposable drugs provide an exciting avenue of research that offer promise for improved treatments for CNS disorders.
International Journal of Environmental Research and Public Health, Volume 18; https://doi.org/10.3390/ijerph182111711

Abstract:
Pandemic of coronavirus disease (COVID-19) is still pressing the healthcare systems worldwide. Thus far, the lack of available COVID-19-targeted treatments has led scientists to look through drug repositioning practices and exploitation of available scientific evidence for potential efficient drugs that may block biological pathways of SARS-CoV-2. Till today, several molecules have emerged as promising pharmacological agents, and more than a few medication protocols are applied during hospitalization. On the other hand, given the criticality of the disease, it is important for healthcare providers, especially those in COVID-19 clinics (i.e., nursing personnel and treating physicians), to recognize potential drug interactions that may lead to adverse drug reactions that may negatively impact the therapeutic outcome. In this review, focusing on patients with respiratory diseases (i.e., asthma or chronic obstructive pulmonary disease) that are treated also for COVID-19, we discuss possible drug interactions, their underlying pharmacological mechanisms, and possible clinical signs that healthcare providers in COVID-19 clinics may need to acknowledge as adverse drug reactions due to drug-drug interactions.
, Dilek Tezcan, Sedat Abusoglu, Sema Yilmaz, Fatma Humeyra Yerlikaya, Mustafa Onmaz, Gulsum Abusoglu, Ali Unlu
Published: 7 November 2021
Inflammopharmacology pp 1-11; https://doi.org/10.1007/s10787-021-00887-8

The publisher has not yet granted permission to display this abstract.
Rebecca L. Pedler,
Published: 2 November 2021
Reviews in Medical Virology; https://doi.org/10.1002/rmv.2310

The publisher has not yet granted permission to display this abstract.
, George R. Smith, Uddhav Timilsina, , Ram Samudrala, Spyridon Stavrou,
Published: 7 October 2021
Antiviral Research, Volume 195; https://doi.org/10.1016/j.antiviral.2021.105183

The publisher has not yet granted permission to display this abstract.
Saima Reyaz, Alvea Tasneem, Gyan Prakash Rai,
Journal of Molecular Graphics and Modelling, Volume 109; https://doi.org/10.1016/j.jmgm.2021.108021

The publisher has not yet granted permission to display this abstract.
Osamu Yoshida, Yoichi Hiasa, Julio C Aguilar, Eduardo Penton, Sakirul I Khan, , Mamun A Mahtab, H Uddin, Guillen N Gerardo
Euroasian Journal of Hepato-Gastroenterology, Volume 11, pp 27-31; https://doi.org/10.5005/jp-journals-10018-1341

Abstract:
Akbar SMF, Mahtab MA, Aguilar JC, et al. Role of Pegylated Interferon in Patients with Chronic Liver Diseases in the Context of SARS-CoV-2 Infection. Euroasian J Hepato-Gastroenterol 2021;11(1):27–31.
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