FASEB J. 2022 Feb;36(2):e22148. doi: 10.1096/fj.202101447R.

ABSTRACT

Thymic stromal lymphopoietin (TSLP), a type I cytokine belonging to the IL-2 cytokine family, promotes Th2-mediated inflammatory responses. The aim of this study is to investigate whether TSLP increases inflammatory responses via induction of autophagy using a murine T cell lymphoma cell line, EL4 cells, and lipopolysaccharide (LPS)-injected mice. TSLP increased expression levels of autophagy-related factors, such as Beclin-1, LC3-II, p62, Atg5, and lysosome associated membrane protein 1/2, whereas these factors increased by TSLP disappeared by neutralization of TSLP in EL4 cells. TSLP activated JAK1/JAK2/STAT5/JNK/PI3K, while the blockade of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways reduced the expression levels of Beclin-1, LC3-II, and p62 in TSLP-stimulated EL4 cells. In addition, TSLP simultaneously increased levels of inflammatory cytokines via induction of autophagy by activation of JAK1/JAK2/STAT5/JNK/PI3K signaling pathways. In an LPS-induced acute liver injury (ALI) mouse model, exogenous TSLP increased expression levels of Beclin-1 and LC3-II, whereas functional deficiency of TSLP by TSLP siRNA resulted in lower expression of Beclin-1, LC3-II, and inflammatory cytokines, impairing their ability to form autophagosomes in ALI mice. Thus, our findings show a new role of TSLP between autophagy and inflammatory responses. In conclusion, regulating TSLP-induced autophagy may be a potential therapeutic strategy for inflammatory responses.

PMID:34997949 | DOI:10.1096/fj.202101447R

Mol Psychiatry. 2022 Jan 7. doi: 10.1038/s41380-021-01432-3. Online ahead of print.

ABSTRACT

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) accelerates the discovery of prophylactic and therapeutic drugs for persons infected with the virus. Drug repurposing for the COVID-19 pandemic has received particular attention. Increasing clinical data suggest that antidepressant use in early-stage subjects with COVID-19 might be associated with a reduced risk of intubation or death. Among the antidepressants, fluvoxamine is the most attractive drug for mild to moderate subjects with COVID-19. In this article, we review the mechanisms of action (i.e., serotonin transporter, sigma-1 receptor, and acid sphingomyelinase) of fluvoxamine for COVID-19. Furthermore, we discuss a possible link between maternal COVID-19 infection and a risk for neuropsychiatric disorders (i.e., autism spectrum disorder and schizophrenia) in offspring.

PMID:34997196 | DOI:10.1038/s41380-021-01432-3

Precis Clin Med. 2021 Aug 28;4(4):215-230. doi: 10.1093/pcmedi/pbab022. eCollection 2021 Dec.

ABSTRACT

Coronavirus disease 2019 (COVID-19) has impacted almost every part of human life worldwide, posing a massive threat to human health. The lack of time for new drug discovery and the urgent need for rapid disease control to reduce mortality have led to a search for quick and effective alternatives to novel therapeutics, for example drug repurposing. To identify potentially repurposable drugs, we employed a systematic approach to mine candidates from U.S. FDA-approved drugs and preclinical small-molecule compounds by integrating gene expression perturbation data for chemicals from the Library of Integrated Network-Based Cellular Signatures project with a publicly available single-cell RNA sequencing dataset from patients with mild and severe COVID-19 (GEO: GSE145926, public data available and accessed on 22 April 2020). We identified 281 FDA-approved drugs that have the potential to be effective against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 16 of which are currently undergoing clinical trials to evaluate their efficacy against COVID-19. We experimentally tested and demonstrated the inhibitory effects of tyrphostin-AG-1478 and brefeldin-a, two chemical inhibitors of glycosylation (a post-translational modification) on the replication of the single-stranded ribonucleic acid (ssRNA) virus influenza A virus as well as on the transcription and translation of host cell cytokines and their regulators (IFNs and ISGs). In conclusion, we have identified and experimentally validated repurposable anti-SARS-CoV-2 and IAV drugs using a systems biology approach, which may have the potential for treating these viral infections and their complications (sepsis).

PMID:34993416 | PMC:PMC8694063 | DOI:10.1093/pcmedi/pbab022

Front Pharmacol. 2021 Dec 21;12:768023. doi: 10.3389/fphar.2021.768023. eCollection 2021.

ABSTRACT

Rare diseases are life-threatening or chronically debilitating low-prevalent disorders caused by pathogenic mutations or particular environmental insults. Due to their high complexity and low frequency, important gaps still exist in their prevention, diagnosis, and treatment. Since new drug discovery is a very costly and time-consuming process, leading pharmaceutical companies show relatively low interest in orphan drug research and development due to the high cost of investments compared to the low market return of the product. Drug repurposing-based approaches appear then as cost- and time-saving strategies for the development of therapeutic opportunities for rare diseases. In this article, we discuss the scientific, regulatory, and economic aspects of the development of repurposed drugs for the treatment of rare neurodegenerative disorders with a particular focus on Huntington's disease, Friedreich's ataxia, Wolfram syndrome, and amyotrophic lateral sclerosis. The role of academia, pharmaceutical companies, patient associations, and foundations in the identification of candidate compounds and their preclinical and clinical evaluation will also be discussed.

PMID:34992533 | PMC:PMC8724568 | DOI:10.3389/fphar.2021.768023

Infect Drug Resist. 2021 Dec 21;14:5575-5593. doi: 10.2147/IDR.S338987. eCollection 2021.

ABSTRACT

Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health and attracted the attention of the World Health Organization (WHO) and the governments of various countries. Therefore, the establishment of measures against bacterial resistance and the discovery of new antibacterial drugs are increasingly urgent to better contain the emergence of bacterial resistance and provide a reference for the development of new antibacterial drugs. In this review, we discuss some antibiotic drugs that have been approved for clinical use and a partial summary of the meaningful research results of anti-drug resistant bacterial drugs in different fields, including the antibiotic drugs approved by the FDA from 2015 to 2020, the potential drugs against drug-resistant bacteria, the new molecules synthesized by chemical modification, combination therapy, drug repurposing, immunotherapy and other therapies.

PMID:34992385 | PMC:PMC8711564 | DOI:10.2147/IDR.S338987

Parasit Vectors. 2022 Jan 7;15(1):10. doi: 10.1186/s13071-021-05127-0.

ABSTRACT

BACKGROUND: Drug resistance and toxic side effects are major challenges in the treatment of babesiosis. As such, new drugs are needed to combat the emergence of drug resistance in Babesia parasites and to develop alternative treatment strategies. A combination of naphthoquine (NQ) and artemisinin is an antimalarial therapy in pharmaceutical markets. The present study repurposed NQ as a drug for the treatment of babesiosis by evaluating the anti-Babesia activity of naphthoquine phosphate (NQP) alone.

METHODS: An in vitro growth inhibition assay of NQP was tested on Babesia gibsoni cultures using a SYBR Green I-based fluorescence assay. In addition, the in vivo growth inhibitory effect of NQP was evaluated using BALB/c mice infected with Babesia rodhaini. The parasitemia level and hematocrit values were monitored to determine the therapeutic efficacy of NQP and the clinical improvements in NQP-treated mice.

RESULTS: The half maximal inhibitory concentration of NQP against B. gibsoni in vitro was 3.3 ± 0.5 μM. Oral administration of NQP for 5 consecutive days at a dose of 40 mg/kg of body weight resulted in significant inhibition of B. rodhaini growth in mice as compared with that of the control group. All NQP-treated mice survived, whereas the mice in the control group died between days 6 and 9 post-infection.

CONCLUSION: This is the first study to evaluate the anti-Babesia activity of NQP in vitro and in vivo. Our findings suggest that NQP is a promising drug for treating Babesia infections, and drug repurposing may provide new treatment strategies for babesiosis.

PMID:34991686 | DOI:10.1186/s13071-021-05127-0

Pharmacol Res. 2022 Jan 3:106055. doi: 10.1016/j.phrs.2021.106055. Online ahead of print.

ABSTRACT

Polypharmacology is a concept where a molecule can interact with two or more targets simultaneously. It offers many advantages as compared to the conventional single targeting molecules. A multi-targeting drug is much more efficacious due to its cumulative efficacy at all of its individual targets making it much more effective in complex and multifactorial diseases like cancer, where multiple proteins and pathways are involved in the onset and development of the disease. For a molecule to be polypharmacologic in nature, it needs to possess promiscuity which is the ability to interact with multiple targets; and at the same time avoid binding to antitargets which would otherwise result in off-target adverse effects. There are certain structural features and physicochemical properties which when present would help researchers to predict if the designed molecule would possess promiscuity or not. Promiscuity canalso be identified via advanced state-of-the-art computational methods. In this review, we also elaborate on the methods by which one can intentionally incorporate promiscuity in their molecules and make them polypharmacologic. The polypharmacology paradigm of "one drug-multiple targets" has numerous applications especially in drug repurposing where an already established drug is redeveloped for a new indication. Though designing a polypharmacological drug is much more difficult than designing a single-targeting drug, with the current technologies and information regarding different diseases and chemical functional groups, it is plausible for researchers to intentionally design a polypharmacological drug and unlock its advantages.

PMID:34990865 | DOI:10.1016/j.phrs.2021.106055

Assay Drug Dev Technol. 2022 Jan 6. doi: 10.1089/adt.2021.090. Online ahead of print.

ABSTRACT

Cytokine release syndrome, a prominent mechanism of morbidity and mortality in patients with coronavirus disease 2019 (COVID-19), can cause multiple bodily reactions, including excessive release of proinflammatory mediators, with tumor necrosis factor-α (TNF-α) being the most prevalent cytokine combined with persistently elevated D-dimer levels that are indicative of potential thrombotic events, low levels of endogenous nitric oxide (NO) generation, and progressive decrease in hemoglobin production. In our argument, the conceptual repurposing of hydroxyurea (HU) for managing COVID-19 can provide a promising therapeutic option originating from a rich history of investigational antiviral activity. HU as a proposed supportive therapeutic agent for treating COVID-19 can exemplify a successful remedial choice through its anti-inflammatory activity along with an intrinsic propensity to control the circulatory levels of key cytokines including TNF-α. HU has the ability to undergo in vivo NO conversion acting as NO donor together with being a prominent inducer of fetal hemoglobin (HbF) production. The combination of the mentioned two properties allows HU to possess evident capability of protecting against thrombotic events by controlling D-dimer levels. The implication of our hypothetical argument sheds light on the curative potential of HU, which can be strategically harnessed against COVID-19.

PMID:34990284 | DOI:10.1089/adt.2021.090

Emerg Microbes Infect. 2022 Jan 6:1-29. doi: 10.1080/22221751.2022.2026739. Online ahead of print.

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has set off a global pandemic. There is an urgent unmet need for safe, affordable, and effective therapeutics against COVID-19. In this regard, drug repurposing is considered as a promising approach. We assessed the compounds that affect the endosomal acidic environment by applying human angiotensin-converting enzyme 2 (hACE2)-expressing cells infected with a SARS-CoV-2 spike (S) protein-pseudotyped HIV reporter virus and identified that obatoclax resulted in the strongest inhibition of S-protein-mediated virus entry. The potent antiviral activity of obatoclax at nanomolar concentrations was confirmed in different human lung and intestinal cells infected with the SARS-CoV-2 pseudotype system as well as clinical virus isolates. Furthermore, we uncovered that obatoclax executes a double-strike against SARS-CoV-2. It prevented SARS-CoV-2 entry by blocking endocytosis of virions through diminished endosomal acidification and the corresponding inhibition of the enzymatic activity of the endosomal cysteine protease cathepsin L. Additionally, obatoclax impaired the SARS-CoV-2 S-mediated membrane fusion by targeting the MCL-1 protein and reducing furin protease activity. In accordance with these overarching mechanisms, obatoclax blocked the virus entry mediated by different S proteins derived from several SARS-CoV-2 variants of concern such as, Alpha (B.1.1.7), Beta (B.1.351), and Delta (B.1.617.2). Taken together, our results identified obatoclax as a novel effective antiviral compound that keeps SARS-CoV-2 at bay by blocking both endocytosis and membrane fusion. Our data suggested that obatoclax should be further explored as clinical drug for the treatment of COVID-19.

PMID:34989664 | DOI:10.1080/22221751.2022.2026739

Artif Intell Life Sci. 2021 Dec;1:100020. doi: 10.1016/j.ailsci.2021.100020. Epub 2021 Dec 17.

ABSTRACT

Despite available vaccinations COVID-19 case numbers around the world are still growing, and effective medications against severe cases are lacking. In this work, we developed a machine learning model which predicts mortality for COVID-19 patients using data from the multi-center 'Lean European Open Survey on SARS-CoV-2-infected patients' (LEOSS) observational study (>100 active sites in Europe, primarily in Germany), resulting into an AUC of almost 80%. We showed that molecular mechanisms related to dementia, one of the relevant predictors in our model, intersect with those associated to COVID-19. Most notably, among these molecules was tyrosine kinase 2 (TYK2), a protein that has been patented as drug target in Alzheimer's Disease but also genetically associated with severe COVID-19 outcomes. We experimentally verified that anti-cancer drugs Sorafenib and Regorafenib showed a clear anti-cytopathic effect in Caco2 and VERO-E6 cells and can thus be regarded as potential treatments against COVID-19. Altogether, our work demonstrates that interpretation of machine learning based risk models can point towards drug targets and new treatment options, which are strongly needed for COVID-19.

PMID:34988543 | PMC:PMC8677630 | DOI:10.1016/j.ailsci.2021.100020

Brain Commun. 2021 Dec 4;3(4):fcab287. doi: 10.1093/braincomms/fcab287. eCollection 2021.

ABSTRACT

Better drugs are needed for common epilepsies. Drug repurposing offers the potential of significant savings in the time and cost of developing new treatments. In order to select the best candidate drug(s) to repurpose for a disease, it is desirable to predict the relative clinical efficacy that drugs will have against the disease. Common epilepsy can be divided into different types and syndromes. Different antiseizure medications are most effective for different types and syndromes of common epilepsy. For predictions of antiepileptic efficacy to be clinically translatable, it is essential that the predictions are specific to each form of common epilepsy, and reflect the patterns of drug efficacy observed in clinical studies and practice. These requirements are not fulfilled by previously published drug predictions for epilepsy. We developed a novel method for predicting the relative efficacy of drugs against any common epilepsy, by using its Genome-Wide Association Study summary statistics and drugs' activity data. The methodological advancement in our technique is that the drug predictions for a disease are based upon drugs' effects on the function and abundance of proteins, and the magnitude and direction of those effects, relative to the importance, degree and direction of the proteins' dysregulation in the disease. We used this method to predict the relative efficacy of all drugs, licensed for any condition, against each of the major types and syndromes of common epilepsy. Our predictions are concordant with findings from real-world experience and randomized clinical trials. Our method predicts the efficacy of existing antiseizure medications against common epilepsies; in this prediction, our method outperforms the best alternative existing method: area under receiver operating characteristic curve (mean ± standard deviation) 0.83 ± 0.03 and 0.63 ± 0.04, respectively. Importantly, our method predicts which antiseizure medications are amongst the more efficacious in clinical practice, and which antiseizure medications are amongst the less efficacious in clinical practice, for each of the main syndromes of common epilepsy, and it predicts the distinct order of efficacy of individual antiseizure medications in clinical trials of different common epilepsies. We identify promising candidate drugs for each of the major syndromes of common epilepsy. We screen five promising predicted drugs in an animal model: each exerts a significant dose-dependent effect upon seizures. Our predictions are a novel resource for selecting suitable candidate drugs that could potentially be repurposed for each of the major syndromes of common epilepsy. Our method is potentially generalizable to other complex diseases.

PMID:34988442 | PMC:PMC8710935 | DOI:10.1093/braincomms/fcab287

Open Forum Infect Dis. 2021 Dec 17;9(1):ofab581. doi: 10.1093/ofid/ofab581. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Currently, only dexamethasone, tocilizumab, and sarilumab have conclusively been shown to reduce mortality of coronavirus disease 2019 (COVID-19). Safe and effective treatments will need to be both affordable and widely available globally to be used alongside vaccination programs. This analysis will estimate and compare potential generic minimum costs of a selection of approved COVID-19 drug candidates with available international list prices.

METHODS: We searched for repurposed drugs that have been approved by at least one of the World Health Organization, US Food and Drug Administration, or the United Kingdom National Institute of Health and Care Excellence organizations or at least given emergency use authorization or recommended for off-label prescription. Drug prices were searched for dexamethasone, budesonide, baricitinib, tocilizumab, casirivimab, and imdevimab, and sarilumab, using active pharmaceutical ingredients (APIs) data extracted from global shipping records. This was compared with national pricing data from a range of low-, medium-, and high-income countries. Annual API export volumes from India were used to estimate the current availability of each drug.

RESULTS: Repurposed therapies can be generically manufactured for some treatments at very low per-course costs, ranging from US $2.58 for intravenous (IV) dexamethasone (or US $0.19 orally) and US $4.34 for inhaled budesonide. No export price data were available for baricitinib, tocilizumab, casirivimab, and imdevimab, or sarilumab, but courses of these treatments have higher prices, ranging from US $6.67 for baricitinib to US $875.5 for sarilumab. When comparing international list prices, we found wide variations between countries.

CONCLUSIONS: Successful management of COVID-19 will require equitable access to treatment for all populations, not just those able to pay high prices. Dexamethasone and budesonide are widely available and affordable, whereas monoclonal antibodies and IV treatment courses are more expensive.

PMID:34988252 | PMC:PMC8709896 | DOI:10.1093/ofid/ofab581

Front Oncol. 2021 Dec 20;11:822865. doi: 10.3389/fonc.2021.822865. eCollection 2021.

ABSTRACT

[This corrects the article DOI: 10.3389/fonc.2021.741326.].

PMID:34988031 | PMC:PMC8722216 | DOI:10.3389/fonc.2021.822865

Front Immunol. 2021 Dec 20;12:784989. doi: 10.3389/fimmu.2021.784989. eCollection 2021.

ABSTRACT

Effective treatment strategies for severe coronavirus disease (COVID-19) remain scarce. Hydrolysis of membrane-embedded, inert sphingomyelin by stress responsive sphingomyelinases is a hallmark of adaptive responses and cellular repair. As demonstrated in experimental and observational clinical studies, the transient and stress-triggered release of a sphingomyelinase, SMPD1, into circulation and subsequent ceramide generation provides a promising target for FDA-approved drugs. Here, we report the activation of sphingomyelinase-ceramide pathway in 23 intensive care patients with severe COVID-19. We observed an increase of circulating activity of sphingomyelinase with subsequent derangement of sphingolipids in serum lipoproteins and from red blood cells (RBC). Consistent with increased ceramide levels derived from the inert membrane constituent sphingomyelin, increased activity of acid sphingomyelinase (ASM) accurately distinguished the patient cohort undergoing intensive care from healthy controls. Positive correlational analyses with biomarkers of severe clinical phenotype support the concept of an essential pathophysiological role of ASM in the course of SARS-CoV-2 infection as well as of a promising role for functional inhibition with anti-inflammatory agents in SARS-CoV-2 infection as also proposed in independent observational studies. We conclude that large-sized multicenter, interventional trials are now needed to evaluate the potential benefit of functional inhibition of this sphingomyelinase in critically ill patients with COVID-19.

PMID:34987511 | PMC:PMC8721106 | DOI:10.3389/fimmu.2021.784989

Nat Rev Neurol. 2022 Jan 5. doi: 10.1038/s41582-021-00592-8. Online ahead of print.

ABSTRACT

Cerebral small vessel disease (cSVD) is a leading cause of ischaemic and haemorrhagic stroke and a major contributor to dementia. Covert cSVD, which is detectable with brain MRI but does not manifest as clinical stroke, is highly prevalent in the general population, particularly with increasing age. Advances in technologies and collaborative work have led to substantial progress in the identification of common genetic variants that are associated with cSVD-related stroke (ischaemic and haemorrhagic) and MRI-defined covert cSVD. In this Review, we provide an overview of collaborative studies - mostly genome-wide association studies (GWAS) - that have identified >50 independent genetic loci associated with the risk of cSVD. We describe how these associations have provided novel insights into the biological mechanisms involved in cSVD, revealed patterns of shared genetic variation across cSVD traits, and shed new light on the continuum between rare, monogenic and common, multifactorial cSVD. We consider how GWAS summary statistics have been leveraged for Mendelian randomization studies to explore causal pathways in cSVD and provide genetic evidence for drug effects, and how the combination of findings from GWAS with gene expression resources and drug target databases has enabled identification of putative causal genes and provided proof-of-concept for drug repositioning potential. We also discuss opportunities for polygenic risk prediction, multi-ancestry approaches and integration with other omics data.

PMID:34987231 | DOI:10.1038/s41582-021-00592-8

J Biomol Struct Dyn. 2022 Jan 5:1-9. doi: 10.1080/07391102.2021.2024260. Online ahead of print.

ABSTRACT

Although a certain level of efficacy and safety of several vaccine products against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) have been established, unmet medical needs for orally active small molecule therapeutic drugs are still very high. As a key drug target molecule, SARS-CoV-2 main protease (Mpro) is focused and large number of in-silico screenings, a part of which were supported by artificial intelligence (AI), have been conducted to identify Mpro inhibitors both through drug repurposing and drug discovery approaches. In the many drug-repurposing studies, docking simulation-based technologies have been mainly employed and contributed to the identification of several Mpro binders. On the other hand, because AI-guided INTerprotein's Engine for New Drug Design (AI-guided INTENDD), an AI-supported activity prediction system for small molecules, enables to propose the potential binders by proprietary AI scores but not docking scores, it was expected to identify novel potential Mpro binders from FDA-approved drugs. As a result, we selected 20 potential Mpro binders using AI-guided INTENDD, of which 13 drugs showed Mpro-binding signal by surface plasmon resonance (SPR) method. Six (6) compounds among the 13 positive drugs were identified for the first time by the present study. Furthermore, it was verified that vorapaxar bound to Mpro with a Kd value of 27 µM by SPR method and inhibited virus replication in SARS-CoV-2 infected cells with an EC50 value of 11 µM.Communicated by Ramaswamy H. Sarma.

PMID:34984963 | DOI:10.1080/07391102.2021.2024260

Orphanet J Rare Dis. 2022 Jan 4;17(1):1. doi: 10.1186/s13023-021-02091-x.

ABSTRACT

BACKGROUND: The development of new therapies may rely on the conduct of human experimentation as well as later clinical trials of therapeutic interventions. Ethical considerations seek to protect the patient from risk but few have sought to ascertain the attitude to such risk of patients with progressive debilitating or terminal conditions, for which no mitigating or curative therapies exist. Such understanding is also important if recruitment is to be maximized. We therefore sought to define the motivations for and barriers to trial participation amongst patients with progressive ataxias, as well as their condition-specific trial preferences.

METHODS: We conducted an online survey consisting of 29 questions covering four key domains (demographics, personal motivation, drug therapy and study design) relating to the design of clinical trials. Two major ataxia charities, Ataxia UK and the Friedreich's Ataxia Research Alliance (FARA) sent the survey to their members. Responses were analysed by disease and by ambulatory status.

RESULTS: Of 342 respondents, 204 reported a diagnosis of Friedreich's ataxia (FRDA), 55 inherited cerebellar ataxia (CA) and 70 idiopathic CA. The most important symptoms to be addressed by a trial were considered to be balance problems and ambulation, although these were superseded by speech problems in wheelchair users. Common motivations for participation were potential benefits to self and others. Reasons for non-participation included concerns about side effects, and the burden and cost of travel. Financial reimbursement for expenses was reported to be likely to increase trial engagement, Phase two trials were the most popular to participate in, and the use of a placebo arm was seen as a disincentive. Across all disease subgroups, drug repurposing trials proved popular and just under 70% of participants would be prepared to undergo intrathecal drug administration.

CONCLUSIONS: Knowledge of motivations for and barriers to trial participation as well as the acceptability of investigations, time commitments and routes of drug administration should inform better, more patient focused trial design. This in turn may improve recruitment and retention of participants to future trials.

PMID:34983593 | DOI:10.1186/s13023-021-02091-x

Nihon Yakurigaku Zasshi. 2022;157(1):41-46. doi: 10.1254/fpj.21042.

ABSTRACT

Although months have passed since WHO declared COVID-19 a global pandemic, only a limited number of clinically effective drugs are available, and the development of drugs to treat COVID-19 has become an urgent issue worldwide. The pace of new research on COVID-19 is extremely high and it is impossible to read every report. In order to tackle these problems, we leveraged our artificial intelligence (AI) system, Concept Encoder, to accelerate the process of drug repositioning. Concept Encoder is a patented AI system based on natural language processing technology and by deeply learning papers on COVID-19, the system identified a large group of genes implicated in COVID-19 pathogenesis. The AI system then generated a molecular linkage map for COVID-19, connecting the genes by learning the molecular relationship comprehensively. By thoroughly reviewing the resulting map and list of the genes with rankings, we found potential key players for disease progression and existing drugs that might improve COVID-19 survival. Here, we focus on potential targets and discuss the perspective of our approach.

PMID:34980812 | DOI:10.1254/fpj.21042

Nihon Yakurigaku Zasshi. 2022;157(1):38-40. doi: 10.1254/fpj.21041.

ABSTRACT

Eritoran (E5564) is Eisai's in-house discovered and developed investigational Toll-Like Receptor 4 (TLR4) antagonist created with natural product organic synthesis technology. It is a structural analogue of Lipid A, which is an activator of endotoxins of bacteria. It has been previously observed to be safe in 14 clinical studies including a large Phase 3 randomized trial in severe sepsis. In order to evaluate therapeutic efficacy by eritoran, we are participating in the international network REMAP-CAP-COVID (Randomized, Embedded, Multi-factorial, Adaptive Platform-Community Acquired Pneumonia COVID) which aims for novel coronavirus medicine development through drug repurposing, and began an international collaborative clinical trial in October 2020 which is designated for confirmed novel coronavirus patients who are hospitalized and are in a progressing disease state. It is hoped that through suppressing the most upstream TLR4 activity which controls production of multiple cytokines by eritoran, the cytokine storm in patients can be suppressed and pneumonia can thus be prevented from becoming severe. On the other hand, E6011 is the only humanized anti-fractalkine (FKN) monoclonal antibody in the world created by KAN Research Institute. E6011 inhibits the tight binding of CD16-positive monocytes (a cell population that highly expresses the FKN receptor CX3CR1) to vascular endothelial cells, which are important for the local inflammatory response. This is expected to suppress the formation and exacerbation of vasculopathy in COVID-19.

PMID:34980810 | DOI:10.1254/fpj.21041

Nihon Yakurigaku Zasshi. 2022;157(1):27-30. doi: 10.1254/fpj.21043.

ABSTRACT

The new coronavirus (SARS-CoV-2) spread throughout the world and caused a pandemic with COVID-19, an infection caused by SARS-CoV-2. Even today, an increase in the number of cases has also been observed in Japan. Since the drugs used in drug repositioning have already been tested for safety and pharmacokinetics in humans, it is possible to skip some development tests, and since the manufacturing method of the drug has already been established, it is possible to shorten the development period and reduce R&D costs. Therefore, the drug repositioning method is one of the methods that should be tried in order to achieve the initial control of a pandemic. In Japan, it has been announced that research and development using drug repositioning has been conducted to date. The following are some of the candidates that have already been identified as COVID-19 therapeutic agents in Japan and are expected to be identified in the future.

PMID:34980807 | DOI:10.1254/fpj.21043