Sci Rep. 2021 Aug 24;11(1):17138. doi: 10.1038/s41598-021-96612-0.

ABSTRACT

Drug repositioning research using transcriptome data has recently attracted attention. In this study, we attempted to identify new target proteins of the urotensin-II receptor antagonist, KR-37524 (4-(3-bromo-4-(piperidin-4-yloxy)benzyl)-N-(3-(dimethylamino)phenyl)piperazine-1-carboxamide dihydrochloride), using a transcriptome-based drug repositioning approach. To do this, we obtained KR-37524-induced gene expression profile changes in four cell lines (A375, A549, MCF7, and PC3), and compared them with the approved drug-induced gene expression profile changes available in the LINCS L1000 database to identify approved drugs with similar gene expression profile changes. Here, the similarity between the two gene expression profile changes was calculated using the connectivity score. We then selected proteins that are known targets of the top three approved drugs with the highest connectivity score in each cell line (12 drugs in total) as potential targets of KR-37524. Seven potential target proteins were experimentally confirmed using an in vitro binding assay. Through this analysis, we identified that neurologically regulated serotonin transporter proteins are new target proteins of KR-37524. These results indicate that the transcriptome-based drug repositioning approach can be used to identify new target proteins of a given compound, and we provide a standalone software developed in this study that will serve as a useful tool for drug repositioning.

PMID:34429474 | DOI:10.1038/s41598-021-96612-0

Cancer Lett. 2021 Aug 21:S0304-3835(21)00412-2. doi: 10.1016/j.canlet.2021.08.023. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide and lacks effective treatment. Herein, we found that the antifungal Natamycin (NAT) exhibits antitumor activity by inducing apoptosis both in vitro and in vivo. Mechanistically, NAT downregulates the expression of Peroxiredoxin 1 (PRDX1) by promoting ubiquitination-mediated degradation, thereby leading to increased reactive oxygen species (ROS) accumulation and subsequent apoptosis. Exogenous overexpression of PRDX1 or N-acetyl-l-cysteine (NAC) pretreatment abrogates NAT-induced cytotoxicity in PLC/PRF/5 and Huh7 cells, suggesting the vital role of ROS in the antitumor properties of NAT. Of note, downregulation of PRDX1 decreases the phosphorylation of AKT, thereby inducing cytoprotective autophagy and combinational use of NAT and chloroquine (CQ) achieves better anti-tumor efficacy. Moreover, NAT acts synergistically with sorafenib (SOR) in HCC suppression. Collectively, our study provides an important molecular basis for NAT-induced cell death and suggests that the antifungal NAT holds the potential to be repurposed as an anticancer drug for HCC treatment.

PMID:34428517 | DOI:10.1016/j.canlet.2021.08.023

Eur J Pharmacol. 2021 Aug 21:174436. doi: 10.1016/j.ejphar.2021.174436. Online ahead of print.

ABSTRACT

Leishmaniasis is regarded as a neglected tropical disease by World Health Organization (WHO) and is ranked next to malaria as the deadliest protozoan disease. The primary causative agents of the disease comprise of diverse leishmanial species sharing clinical features ranging from skin abrasions to lethal infection in the visceral organs. As several Leishmania species are involved in infection, the role of accurate diagnosis becomes pivotal in adding new dimensions to anti-leishmanial therapy. Diagnostic methods must be fast, reliable, easy to perform, highly sensitive, and specific to differentiate among similar parasitic diseases. Herein, we present the conventional and recent approaches impended for the disease diagnosis and their sensitivity, specificity, and clinical application in parasite detection. Furthermore, we have also elaborated various new methods to cure leishmaniasis, which include host-directed therapies, drug repurposing, nanotechnology, and combinational therapy. This review addresses novel techniques and innovations in leishmaniasis, which can aid in unraveling new strategies to fight against the deadly infection.

PMID:34428435 | DOI:10.1016/j.ejphar.2021.174436

Pharmacotherapy. 2021 Aug 24. doi: 10.1002/phar.2618. Online ahead of print.

ABSTRACT

BACKGROUND: Influenza viruses are responsible for seasonal epidemics and sporadic pandemics of varying severity in humans and additional treatment options are needed. High-throughput siRNA screens and an in-vivo model demonstrated that dextromethorphan (DM) has antiviral activity as a cellular target for treatment of influenza. This study examined DM usage and hospitalization rates among patients with laboratory-confirmed influenza in a national cohort of United States veterans. We aimed to evaluate the potential drug repurposing of DM as a cellular target for the management of influenza utilizing a large, national claims and electronic health record database.

METHODS: This retrospective drug-disease association cohort study was conducted using data from the Veterans Affairs Informatics and Computing Infrastructure (VINCI). We used a cohort with laboratory-confirmed diagnosis of influenza and international classification of disease (ICD)-9/10 diagnosis codes of fever, cough, influenza, or acute upper respiratory infection in an outpatient setting. The study outcome is inpatient hospitalization (all-cause and respiratory) within 30 days of influenza diagnosis. We estimated the relative risk for all-cause and respiratory hospitalizations using Poisson generalized linear model (GLM) and a greedy nearest neighbor propensity score 1:1 matched sub-analysis for both hospitalization models.

FINDINGS: A total of 18,677 patients met the inclusion and exclusion criteria and were evaluated in our study. The cohorts consisted of 2,801 patients dispensed DM and 15,876 untreated patients (no DM). The Poisson GLM adjusted for covariates demonstrated a relative risk reduction of 34% for all-cause hospitalizations (Relative Risk (RR) 0.66, 95% Confidence Interval (CI) 0.525-0.832) and 40% for respiratory hospitalizations (RR 0.597, 95% CI 0.423-0.843) in patients with influenza treated with DM.

CONCLUSION: Influenza viruses continue to emerge and cause infection (including pandemics) in humans, so there remains a critical need to advance the understanding of influenza treatment. Our results demonstrated reduced hospitalization rates for influenza patients treated with DM. Further research on cellular targets and / or DM are warranted for the treatment of influenza.

PMID:34428315 | DOI:10.1002/phar.2618

IEEE J Biomed Health Inform. 2021 Aug 24;PP. doi: 10.1109/JBHI.2021.3106787. Online ahead of print.

ABSTRACT

The aim of the study described in this paper is to shed more light on disease similarities by analyzing the relationship between categorical proximity in human-curated disease ontologies and proximity of disease modules in the human interactome network. We believe that the biomedical understanding of diseases is on the edge of a radical change. The disease module hypothesis (DMH), with its relevant applications to disease-gene discovery and drug repurposing, is leading the revolution of bio-medical research of the future. Human-curated disease ontologies are widely used for diagnostic evaluation, treatment and data comparisons over time, and clinical decision support. However, the recent results of DMH have so far only marginally influenced the disease categorization principles. For these reasons, we deem it fundamental to systematically analyze the degree of correspondence between the anatomical and histological principles at the basis of current disease ontologies and the pathobiological similarity relations discovered in recent network-based studies. Towards this objective, we define a methodology and related algorithms to automatically induce a hierarchical structure of disease modules from proximity relations in the interactome network, and to align, label and systematically compare this structure with a manually defined disease ontology. We demonstrate that our study has some relevant clinical implications: To identify promising regions of the human interactome where new disease-gene relationships could be discovered, either exploiting data-driven methods or clinical experiments; To identify unexplored molecular relationships among diseases; To extend, correct and refine human-curated taxonomies. To the best of our knowledge, this is the first work that presents a methodology to systematically integrate taxonomic and network-based disease classification principles.

PMID:34428165 | DOI:10.1109/JBHI.2021.3106787

JCO Clin Cancer Inform. 2021 Aug;5:881-896. doi: 10.1200/CCI.21.00040.

ABSTRACT

Cancer Informatics for Cancer Centers (CI4CC) is a grassroots, nonprofit 501c3 organization intended to provide a focused national forum for engagement of senior cancer informatics leaders, primarily aimed at academic cancer centers anywhere in the world but with a special emphasis on the 70 National Cancer Institute-funded cancer centers. This consortium has regularly held topic-focused biannual face-to-face symposiums. These meetings are a place to review cancer informatics and data science priorities and initiatives, providing a forum for discussion of the strategic and pragmatic issues that we faced at our respective institutions and cancer centers. Here, we provide meeting highlights from the latest CI4CC Symposium, which was delayed from its original April 2020 schedule because of the COVID-19 pandemic and held virtually over three days (September 24, October 1, and October 8) in the fall of 2020. In addition to the content presented, we found that holding this event virtually once a week for 6 hours was a great way to keep the kind of deep engagement that a face-to-face meeting engenders. This is the second such publication of CI4CC Symposium highlights, the first covering the meeting that took place in Napa, California, from October 14-16, 2019. We conclude with some thoughts about using data science to learn from every child with cancer, focusing on emerging activities of the National Cancer Institute's Childhood Cancer Data Initiative.

PMID:34428097 | DOI:10.1200/CCI.21.00040

J Biomol Struct Dyn. 2021 Aug 23:1-12. doi: 10.1080/07391102.2021.1967786. Online ahead of print.

ABSTRACT

Global health care emergency caused by a new coronavirus (severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2) demands urgent need to repurpose the approved pharmaceutical drugs. Main protease, Mpro of SARS-CoV-2 draws significant attention as a drug target. Herein, we have screened FDA approved organosulfur drugs (till 2016) and our laboratory synthesized organosulfur and organoselenium compounds (L1-L306) against Mpro-apo using docking followed by classical MD simulations. Additionally, a series of compounds (L307-L364) were chosen from previous experimental studies, which were reported to exhibit inhibitory potentials towards Mpro. We found several organosulfur drugs, particularly Venetoclax (FDA approved organosulfur drug for Leukemia) to be a high-affinity binders to the Mpro of SARS-CoV-2. The results reveal that organosulfur compounds including Venetoclax preferentially bind (non-covalently) to the non-catalytic pocket of the protein located in the dimer interface. We found that the ligand binding is primarily favoured by ligand-protein van der Waals interaction and penalized by desolvation effect. Interestingly, Venetoclax binding alters the local flexibility of Mpro and exerts pronounced effect in the C-terminal as well as two loop regions (Loop-A and Loop-B) that play important roles in catalysis. These findings highlighted the importance of drug repurposing and explored the non-catalytic pockets of Mpro in combating COVID-19 infection in addition to the importance of catalytic binding pocket of the protein.Communicated by Ramaswamy H. Sarma.

PMID:34424151 | DOI:10.1080/07391102.2021.1967786

Heliyon. 2021 Aug 17:e07803. doi: 10.1016/j.heliyon.2021.e07803. Online ahead of print.

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) is responsible for the global COVID-19 pandemic and millions of deaths worldwide. In December 2020, a new alpha strain of SARS-CoV2 was identified in the United Kingdom. It was referred to as VUI 202012/01 (Alpha strain modelled under investigation, 2020, month 12, number 01). The interaction between spike protein and ACE2 receptor is a prerequisite for entering virion into the host cell. The present study is focussed on the spike protein of the SARS-COV 2, involving the comparison of binding affinity of new alpha strain modelled spike with previous strain spike (PDB ID:7DDN) using in silico molecular docking, dynamics and simulation studies. The molecular docking studies of the alpha strain modelled spike protein confirmed its higher affinity for the ACE2 receptor than the spike protein of the dominant strain. Similar computational approaches have also been used to investigate the potency of FDA approved drugs from the ZINC Database against the spike protein of new alpha strain modelled and old ones. The drug molecules which showed strong affinity for both the spike proteins are then subjected to ADME analysis. The low overall binding energy of Conivaptan (-107.503 kJ/mol) and Trosec (-94.029 kJ/mol) is indicative of their strong binding affinities, well supported by interactions with critical residues.

PMID:34423145 | PMC:PMC8367657 | DOI:10.1016/j.heliyon.2021.e07803

Inform Med Unlocked. 2021;25:100702. doi: 10.1016/j.imu.2021.100702. Epub 2021 Aug 18.

ABSTRACT

The novel coronavirus (SARS-CoV-2) has expanded rapidly worldwide. Now it has covered more than 150 countries worldwide. It is referred to as COVID-19. SARS-CoV-2 mainly affects the respiratory systems of humans that can lead up to serious illness or even death in the presence of different comorbidities. However, most COVID-19 infected people show mild to moderate symptoms, and no medication is suggested. Still, drugs of other diseases have been used to treat COVID-19. Nevertheless, the absence of vaccines and proper drugs against the COVID-19 virus has increased the mortality rate. Albeit sex is a risk factor for COVID-19, none of the studies considered this risk factor for identifying biomarkers from the RNASeq count dataset. Men are more likely to undertake severe symptoms with different comorbidities and show greater mortality compared with women. From this standpoint, we aim to identify shared gene signatures between males and females from the human COVID-19 RNAseq count dataset of peripheral blood cells using a robust voom approach. We identified 1341 overlapping DEGs between male and female datasets. The gene ontology (GO) annotation and pathway enrichment analysis revealed that DEGs are involved in various BP categories such as nucleosome assembly, DNA conformation change, DNA packaging, and different KEGG pathways such as cell cycle, ECM-receptor interaction, progesterone-mediated oocyte maturation, etc. Ten hub-proteins (UBC, KIAA0101, APP, CDK1, SUMO2, SP1, FN1, CDK2, E2F1, and TP53) were unveiled using PPI network analysis. The top three miRNAs (mir-17-5p, mir-20a-5p, mir-93-5p) and TFs (PPARG, E2F1 and KLF5) were uncovered. In conclusion, the top ten significant drugs (roscovitine, curcumin, simvastatin, fulvestrant, troglitazone, alvocidib, L-alanine, tamoxifen, serine, and doxorubicin) were retrieved using drug repurposing analysis of overlapping DEGs, which might be therapeutic agents of COVID-19.

PMID:34423108 | PMC:PMC8372456 | DOI:10.1016/j.imu.2021.100702

Curr Med Chem. 2021 Aug 20. doi: 10.2174/0929867328666210820114025. Online ahead of print.

ABSTRACT

BACKGROUND: SARS-CoV-2, which emerged in Wuhan, China, is a new global threat that has killed millions of people and continues to do so. This pandemic has not only threatened human life but has also triggered economic downturns across the world. Researchers have made significant strides in discovering molecular insights into SARS-CoV-2 pathogenesis and developing vaccines, but there is still no successful cure for SARS-CoV-2 infected patients.

OBJECTIVE: The present study has proposed a drug-repositioning pipeline for the design and discovery of an effective fungal-derived bioactive metabolite as a drug candidate against SARS-CoV-2.

METHODS: Fungal derivative "Cordycepin" was selected for this study to investigate the inhibitory properties against RNA-dependent RNA polymerase (RdRp) (PDB ID: 6M71) of SARS-CoV-2. The pharmacological profile, intermolecular interactions, binding energy, and stability of the compound were determined utilizing cheminformatic approaches. Subsequently, molecular dynamic simulation was performed to better understand the binding mechanism of cordycepin to RdRp.

RESULTS: The pharmacological data and retrieved molecular dynamics simulations trajectories suggest excellent drug-likeliness and greater structural stability of cordycepin, while the catalytic residues (Asp760, Asp761), as well as other active site residues (Trp617, Asp618, Tyr619, Trp800, Glu811) of RdRp, showed better stability during the overall simulation span.

CONCLUSION: Promising results of pharmacological investigation along with molecular simulations revealed that cordycepin exhibited strong inhibitory potential against SARS-CoV-2 polymerase enzyme (RdRp). Hence, cordycepin should be highly recommended to test in a laboratory to confirm its inhibitory potential against the SARS-CoV-2 polymerase enzyme (RdRp).

PMID:34420502 | DOI:10.2174/0929867328666210820114025

Diabetes. 2021 Aug 20:dbi200046. doi: 10.2337/dbi20-0046. Online ahead of print.

ABSTRACT

Completion of the Human Genome Project enabled a novel systems- and network-level understanding of biology, but this remains to be applied for understanding the pathogenesis of type 1 diabetes (T1D). We propose that defining the key gene regulatory networks that drive β-cell dysfunction and death in T1D might enable the design of therapies that target the core disease mechanism, namely, the progressive loss of pancreatic β-cells. Indeed, many successful drugs do not directly target individual disease genes but, rather, modulate the consequences of defective steps, targeting proteins located one or two steps downstream. If we transpose this to the T1D situation, it makes sense to target the pathways that modulate the β-cell responses to the immune assault-in relation to signals that may stimulate the immune response (e.g., HLA class I and chemokine overexpression and/or neoantigen expression) or inhibit the invading immune cells (e.g., PDL1 and HLA-E expression)-instead of targeting only the immune system, as it is usually proposed. Here we discuss the importance of a focus on β-cells in T1D, lessons learned from other autoimmune diseases, the "alternative splicing connection," data mining, and drug repurposing to protect β-cells in T1D and then some of the initial candidates under testing for β-cell protection.

PMID:34417266 | DOI:10.2337/dbi20-0046

Eur J Med Chem. 2021 Aug 14;225:113778. doi: 10.1016/j.ejmech.2021.113778. Online ahead of print.

ABSTRACT

Histone lysine-specific demethylase 1 (LSD1) is an important epigenetic modulator, and is implicated in malignant transformation and tumor pathogenesis in different ways. Therefore, the inhibition of LSD1 provides an attractive therapeutic target for cancer therapy. Based on drug repurposing strategy, we screened our in-house chemical library toward LSD1, and found that the EGFR inhibitor erlotinib, an FDA-approved drug for lung cancer, possessed low potency against LSD1 (IC50 = 35.80 μM). Herein, we report our further medicinal chemistry effort to obtain a highly water-soluble erlotinib analog 5k (>100 mg/mL) with significantly enhanced inhibitory activity against LSD1 (IC50 = 0.69 μM) as well as higher specificity. In MGC-803 cells, 5k suppressed the demethylation of LSD1, indicating its cellular activity against the enzyme. In addition, 5k had a remarkable capacity to inhibit colony formation, suppress migration and induce apoptosis of MGC803 cells. Furthermore, in MGC-803 xenograft mouse model, 5k treatment resulted in significant reduction in tumor size by 81.6% and 96.1% at dosages of 40 and 80 mg/kg/d, respectively. Our findings indicate that erlotinib-based analogs provide a novel structural set of LSD1 inhibitors with potential for further investigation, and may serve as novel candidates for the treatment of LSD1-overexpressing cancers.

PMID:34416665 | DOI:10.1016/j.ejmech.2021.113778

Biomed Pharmacother. 2021 Aug 17;142:112029. doi: 10.1016/j.biopha.2021.112029. Online ahead of print.

ABSTRACT

Hepatocellular carcinoma (HCC) is a leading cause of cancer related deaths worldwide. It was suggested that albendazole (ABZ) is a powerful inhibitor of several carcinoma types. However, the bioavailability of ABZ is very poor. Additionally, the mechanisms underlying the antitumor effects of ABZ may go beyond its tubulin-inhibiting activity. Therefore, we aimed to examine the effects of ABZ suspension (i.p. and p.o.) and ABZ-loaded cubosomes (LC) on the diethylnitrosamine-induced HCC in mice. ABZ-loaded nanoparticles exhibited a mean particle size of 48.17 ± 0.65 nm and entrapped 93.26 ± 2.48% of ABZ. The in vivo absorption study confirmed a two-fold improvement in the relative bioavailability compared with aqueous ABZ suspension. Furthermore, the oral administration of ABZ cubosomal dispersion demonstrated regression of tumor production rates that was comparable with ABZ (i.p.). ABZ relieved oxidative stress, improved liver function, and decreased necroinflammation score. The antiangiogenic activity was evident as ABZ effectively downregulated tissue expression of CD34, mRNA expression of CD309 and VEGF at the protein expression level. Besides, lower levels of MMP-9 and CXCR4 indicated antimetastatic activity. ABZ showed a considerable level of apoptotic activity as indicated by increased mRNA expression level of p53 and the increased Bax/BCL-2 ratio and active caspase-3. Additionally, Ki-67 expression levels were downregulated showing an antiproliferative potential. These protective effects contributed to increasing survival rate of diethylnitrosamine-treated mice. These effects found to be mediated via interrupting ERK1/2-HIF-1α-p300/CREB interactions. Therefore, our findings revealed that disrupting ERK1/2-HIF-1α-p300/CREB interplay might create a novel therapeutic target for the management of HCC.

PMID:34416629 | DOI:10.1016/j.biopha.2021.112029

Int J Pharm. 2021 Aug 17:121023. doi: 10.1016/j.ijpharm.2021.121023. Online ahead of print.

ABSTRACT

Up to date, there were no approved drugs against coronavirus (COVID-19) disease that dangerously affects global health and the economy. Repurposing the existing drugs would be a promising approach for COVID-19 management. The antidepressant drugs, selective serotonin reuptake inhibitors (SSRIs) class, have antiviral, anti-inflammatory, and anticoagulant effects, which makes them auspicious drugs for COVID 19 treatment. Therefore, this study aimed to predict the possible therapeutic activity of SSRIs against COVID-19. Firstly, molecular docking studies were performed to hypothesize the possible interaction of SSRIs to the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-COV-2) main protease. Secondly, the candidate drug was loaded in lipid polymer hybrid (LPH) nanoparticles to enhance its activity. The studied SSRIs were Fluoxetine hydrochloride (FH), Atomoxteine, Paroxetine, Nisoxteine, Repoxteine RR, and Repoxteine SS. Interestingly, FH could effectively bind with SARS-COV-2 main protease via hydrogen bond formation with low binding energy (-6.7 kcal/mol). Moreover, the optimization of FH-LPH formulation achieved 65.1±2.7% encapsulation efficiency, 10.3±0.4% loading efficiency, 98.5±3.5 nm particle size, and -10.5±0.45 mV zeta potential. Additionally, it improved cellular internalization in a time-dependent manner with good biocompatibility on Human lung fibroblast (CCD-19Lu) cells. Therefore, the study suggested the potential activity of FH-LPH nanoparticles against the COVID-19 pandemic.

PMID:34416332 | DOI:10.1016/j.ijpharm.2021.121023

ACS Med Chem Lett. 2021 Aug 2;12(8):1333-1341. doi: 10.1021/acsmedchemlett.1c00328. eCollection 2021 Aug 12.

ABSTRACT

In the context of drug repositioning and expanding the existing structure-activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (PfNF54 IC50 = 0.025-0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.

PMID:34413963 | PMC:PMC8366009 | DOI:10.1021/acsmedchemlett.1c00328

Sci Rep. 2021 Aug 19;11(1):16814. doi: 10.1038/s41598-021-96110-3.

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a pandemic. Paucity of information concerning the virus and therapeutic interventions have made SARS-CoV-2 infection a genuine threat to global public health. Therefore, there is a growing need for understanding the molecular mechanism of SARS-CoV-2 infection at cellular level. To address this, we undertook a systems biology approach by analyzing publicly available RNA-seq datasets of SARS-CoV-2 infection of different cells and compared with other lung pathogenic infections. Our study identified several key genes and pathways uniquely associated with SARS-CoV-2 infection. Genes such as interleukin (IL)-6, CXCL8, CCL20, CXCL1 and CXCL3 were upregulated, which in particular regulate the cytokine storm and IL-17 signaling pathway. Of note, SARS-CoV-2 infection strongly activated IL-17 signaling pathway compared with other respiratory viruses. Additionally, this transcriptomic signature was also analyzed to predict potential drug repurposing and small molecule inhibitors. In conclusion, our comprehensive data analysis identifies key molecular pathways to reveal underlying pathological etiology and potential therapeutic targets in SARS-CoV-2 infection.

PMID:34413339 | DOI:10.1038/s41598-021-96110-3

Proc Natl Acad Sci U S A. 2021 Sep 7;118(36):e2105815118. doi: 10.1073/pnas.2105815118.

ABSTRACT

The global spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the associated disease COVID-19, requires therapeutic interventions that can be rapidly identified and translated to clinical care. Traditional drug discovery methods have a >90% failure rate and can take 10 to 15 y from target identification to clinical use. In contrast, drug repurposing can significantly accelerate translation. We developed a quantitative high-throughput screen to identify efficacious agents against SARS-CoV-2. From a library of 1,425 US Food and Drug Administration (FDA)-approved compounds and clinical candidates, we identified 17 hits that inhibited SARS-CoV-2 infection and analyzed their antiviral activity across multiple cell lines, including lymph node carcinoma of the prostate (LNCaP) cells and a physiologically relevant model of alveolar epithelial type 2 cells (iAEC2s). Additionally, we found that inhibitors of the Ras/Raf/MEK/ERK signaling pathway exacerbate SARS-CoV-2 infection in vitro. Notably, we discovered that lactoferrin, a glycoprotein found in secretory fluids including mammalian milk, inhibits SARS-CoV-2 infection in the nanomolar range in all cell models with multiple modes of action, including blockage of virus attachment to cellular heparan sulfate and enhancement of interferon responses. Given its safety profile, lactoferrin is a readily translatable therapeutic option for the management of COVID-19.

PMID:34413211 | DOI:10.1073/pnas.2105815118

Front Artif Intell. 2021 Aug 2;4:711467. doi: 10.3389/frai.2021.711467. eCollection 2021.

ABSTRACT

Drug labeling contains an 'INDICATIONS AND USAGE' that provides vital information to support clinical decision making and regulatory management. Effective extraction of drug indication information from free-text based resources could facilitate drug repositioning projects and help collect real-world evidence in support of secondary use of approved medicines. To enable AI-powered language models for the extraction of drug indication information, we used manual reading and curation to develop a Drug Indication Classification and Encyclopedia (DICE) based on FDA approved human prescription drug labeling. A DICE scheme with 7,231 sentences categorized into five classes (indications, contradictions, side effects, usage instructions, and clinical observations) was developed. To further elucidate the utility of the DICE, we developed nine different AI-based classifiers for the prediction of indications based on the developed DICE to comprehensively assess their performance. We found that the transformer-based language models yielded an average MCC of 0.887, outperforming the word embedding-based Bidirectional long short-term memory (BiLSTM) models (0.862) with a 2.82% improvement on the test set. The best classifiers were also used to extract drug indication information in DrugBank and achieved a high enrichment rate (>0.930) for this task. We found that domain-specific training could provide more explainable models without performance sacrifices and better generalization for external validation datasets. Altogether, the proposed DICE could be a standard resource for the development and evaluation of task-specific AI-powered, natural language processing (NLP) models.

PMID:34409286 | PMC:PMC8366025 | DOI:10.3389/frai.2021.711467

Genet Test Mol Biomarkers. 2021 Aug;25(8):563-570. doi: 10.1089/gtmb.2021.0031.

ABSTRACT

Aims: HbE/β-thalassemia is the most prevalent form of severe β-thalassemia in Asian countries. Hydroxyurea (HU) is the most common drug used for the management of sickle-cell anemia but not thalassemia. In this study, we aimed to assess clinical HU response among the Bengali HbE/β-thalassemia patients with respect to the XmnI γGglobin polymorphism and elucidate the association between this polymorphism and HU response efficacy. Materials and Methods: We enrolled 49 transfusion-dependent patients with HbE/β-thalassemia. Fetal hemoglobin levels were measured using high-performance liquid chromatography and complete blood counts were determined pre- and post-HU therapy. Polymerase chain reaction-restriction fragment length polymorphism analyses were performed for genotyping the XmnI γGglobin polymorphism. Results: A total of 30 (61.22%) patients were found to be responders, whereas the remaining 19 (38.78%) were nonresponders. We found 33 patients with the heterozygous (C/T) and three with the homozygous mutant (T/T) genotype status. We obtained a statistically significant correlation (p < 0.001) between the XmnI polymorphism genotype and transfusion-free interval. Patients with the XmnI polymorphism were found to be good responders for HU therapy and showed increased hemoglobin levels. Conclusions: Our findings indicate that HU is a potential drug candidate for thalassemia management, particularly for HbE/β-thalassemia. These results hold implications in repurposing HU as an effective and efficient therapy for HbE/β-thalassemia.

PMID:34406845 | DOI:10.1089/gtmb.2021.0031

Future Microbiol. 2021 Aug 18. doi: 10.2217/fmb-2020-0310. Online ahead of print.

ABSTRACT

Aim: This study was conducted to explore the antibacterial potential of selective estrogen receptor modulators (SERMs). Materials & methods: The percentage growth retardation, bacterial growth kinetics, biofilm, checkerboard and bacterial burden assays were conducted to check antibacterial potential of SERMs. Finally, docking study was also conducted to predict possible antibacterial mechanism of SERMs. Results: In vitro and in vivo studies have shown the antibacterial activity of SERMs against different tested strains of bacteria. The synergistic activity of SERMs in combination with standard antibacterial agents was also observed and tested further under in vivo conditions. In vivo results have shown decreased bacterial bioburden. Docking studies have predicted the multimodal antibacterial mechanism of SERMs. Conclusion: SERMs can be considered as promising broad-spectrum antibacterial agents.

PMID:34406075 | DOI:10.2217/fmb-2020-0310