Pharmacol Res Perspect. 2021 Aug;9(4):e00808. doi: 10.1002/prp2.808.

ABSTRACT

Trial data support an absence of an exposure-survival relationship for pembrolizumab. As these relationships remain unexamined in a real-world setting, we determined them in metastatic melanoma prospectively in an observational study. Translational objectives included identifying biomarkers of progressive disease (PD). Checkpoint blockade naïve patients receiving 2 mg/kg Q3W pembrolizumab had pharmacokinetic and clinical outcome data collected. Trough, a valid surrogate for drug exposure, was assessed using ELISA. T-cell exhaustion and chemokine markers were determined using flow cytometry. Geometric means of exposures and biomarkers were tested against objective response groups using one-way ANOVA. The cohort was split by the median into high versus low pembrolizumab exposure groups. Kaplan-Meier progression-free survival (PFS) and overall survival (OS) curves were estimated for high versus low exposure, compared using the log rank test. The high pembrolizumab exposure group (n = 14) experienced substantially longer median OS (not reached vs. 48 months, p = .014), than the low exposure group (n = 14). A similar positive exposure PFS relationship was found (median not reached vs. 48 months, p = .045). The frequency of TIM-3 expression on CD4+ T cells was significantly higher in PD (mean 27.8%) than complete response (CR) (13.38%, p = .01) and partial response (12.4%, p = .05). There was a near doubling of CXCR6 and TIM-3 co-expression on CD4+ T cells in PD (mean 23.3%) versus CR (mean 11.4, p = .003) and partial response (9.8%, p = .0001). We describe positive exposure-PFS and exposure-OS relationships for pembrolizumab in metastatic melanoma. TIM-3, alongside co-expression of CXCR6 and TIM-3 on circulating CD4+ T cells are potential bio markers of treatment failure.

PMID:34129290 | DOI:10.1002/prp2.808

Br J Pharmacol. 2021 Jun 14. doi: 10.1111/bph.15594. Online ahead of print.

ABSTRACT

Since the start of the coronavirus SARS-Cov-2 pandemic, a disease that has become one of the world's greatest global health challenges, the role of the immune system has been at the forefront of scientific studies. The pathophysiology of COVID-19 is complex, which is evident in those at higher risk for poor outcome. Multiple systems contribute to thrombosis and inflammation seen in COVID-19 patients, including neutrophil and platelet activation, and endothelial dysfunction. Understanding how the immune system functions in different patient cohorts (particularly given recent emerging events with the Oxford/AstraZeneca vaccine) is vital to understanding the pathophysiology of this devastating disease and for the subsequent development of novel therapeutic targets and to facilitate possible drug repurposing strategies that could benefit society on a global scale.

PMID:34128218 | DOI:10.1111/bph.15594

Syst Biol Reprod Med. 2021 Jun 14:1-17. doi: 10.1080/19396368.2021.1928792. Online ahead of print.

ABSTRACT

Embryo implantation is one of the most inefficient steps in assisted reproduction, so the identifying drugs with a potential clinical application to improve it has a strong interest. This work applies artificial intelligence and systems biology-based mathematical modeling strategies to unveil potential treatments by computationally analyzing and integrating available molecular and clinical data from patients. The mathematical models of embryo implantation computationally generated here simulate the molecular networks underneath this biological process. Once generated, these models were analyzed in order to identify potential repositioned drugs (drugs already used for other indications) able to improve embryo implantation by modulating the molecular pathways involved. Interestingly, the repositioning analysis has identified drugs considering two endpoints: (1) drugs able to modulate the activity of proteins whose role in embryo implantation is already bibliographically acknowledged, and (2) drugs that modulate key proteins in embryo implantation previously predicted through a mechanistic analysis of the mathematical models. This second approach increases the scope open for examination and potential novelty of the repositioning strategy. As a result, a list of 23 drug candidates to improve embryo implantation after IVF was identified by the mathematical models. This list includes many of the compounds already tested for this purpose, which reinforces the predictive capacity of our approach, together with novel repositioned candidates (e.g., Infliximab, Polaprezinc, and Amrinone). In conclusion, the present study exploits existing molecular and clinical information to offer new hypotheses regarding molecular mechanisms in embryo implantation and therapeutic candidates to improve it. This information will be very useful to guide future research.Abbreviations: IVF: in vitro fertilization; EI: Embryo implantation; TPMS: Therapeutic Performance Mapping System; MM: mathematical models; ANN: Artificial Neuronal Networks; TNFα: tumour necrosis factor factor-alpha; HSPs: heat shock proteins; VEGF: vascular endothelial growth factor; PPARA: peroxisome proliferator activated receptor-α PXR: pregnane X receptor; TTR: transthyretin; BED: Biological Effectors Database; MLP: multilayer perceptron.

PMID:34126818 | DOI:10.1080/19396368.2021.1928792

Front Oncol. 2021 May 28;11:579488. doi: 10.3389/fonc.2021.579488. eCollection 2021.

ABSTRACT

Drug repositioning is a promising and powerful innovative strategy in the field of drug discovery. In this study, we screened a compound-library containing 800 Food and Drug Administration approved drugs for their anti-leukemic effect. All screening activities made use of human peripheral blood mononuclear cells (PBMCs), isolated from healthy or leukemic donors. Compounds with confirmed cytotoxicity were selected and classified in three groups: i) anti-neoplastic compounds which are drugs used in leukemia treatment, ii) compounds known to have an anti-cancer effect and iii) compounds demonstrating an anti-leukemic potential for the first time. The latter group was the most interesting from a drug repositioning perspective and yielded a single compound, namely Isoprenaline which is a non-selective β-adrenergic agonist. Analysis of the cytotoxic effect of this drug indicated that it induces sustainable intracellular ATP depletion leading, over time, to necrotic cell death. We exploited the Isoprenaline-induced intracellular ATP depletion to sensitize primary leukemic cells to fludarabine (purine analogue) and Ibrutinib (Bruton's tyrosine kinase inhibitor) treatment. In-vitro treatment of primary leukemic cells with a combination of Isoprenaline/fludarabine or Isoprenaline/Ibrutinib showed a very high synergistic effect. These combinations could constitute a new efficient regimen for CLL treatment following successful evaluation in animal models and clinical trials.

PMID:34123769 | PMC:PMC8195271 | DOI:10.3389/fonc.2021.579488

Biocatal Agric Biotechnol. 2021 Jun 7:102056. doi: 10.1016/j.bcab.2021.102056. Online ahead of print.

ABSTRACT

The recent outbreak of COVID-19 is attributed to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). This viral disease is rapidly spreading across the globe, including India. The mainstay in managing the disease is supportive care, nutrition, and preventing further progression in the absence of proven antiviral drugs. Currently two vaccines Covishield and Covaxin are administered in India. Long-term plans of developing most reliable mRNA-based vaccines are also underway for the future method of prophylaxis. The Siddha system of medicine's holistic approach emphasizes lifestyle modification, prophylactic interventions, and dietary management to boost the host immunity and treatment with herbal medicines and higher-order medicines as the case may be. In this review, a brief outline of the disease COVID-19, Coronavirus, evidence-based traditional Siddha interventions for respiratory ailments, immune boosters highlighting the relevant published research on individual herbs are dealt, which pave way for further research on drug repurposing for COVID-19. Historical evidence on the prevention and treatment of infections in Siddha classics is studied. Web search in databases such as Embase, Biomed Central Articles, Pub med, NLM, Web of Science CrossRef, Google scholar, AYUSH research portal, google search engine related to antiviral properties of herbs used in the preparation of Siddha drugs was also carried out.

PMID:34122672 | PMC:PMC8180453 | DOI:10.1016/j.bcab.2021.102056

Drug Deliv. 2021 Dec;28(1):1188-1203. doi: 10.1080/10717544.2021.1937383.

ABSTRACT

Studies have shown the use of non-steroidal anti-inflammatory drugs, such as ibuprofen could reduce the risk of Alzheimer's disease. The drug-repurposing strategy offers a bright opportunity for these patients. Intranasal administration through the olfactory pathway provides noninvasive and direct drug delivery to the target brain. A novel ibuprofen microemulsion was prepared, characterized and assessed the brain uptake in rats. The solubility of ibuprofen in various oils, surfactants, co-surfactants, and different ratios of surfactant/co-surfactant mixtures was screened and the phase diagrams were constructed. The colloidal particle size was 166.3 ± 2.55 nm and the zeta potential was -22.7 mV. Conductivity and dilution test identified an O/W type microemulsion with pH 4.09 ± 0.08. The rheological study showed a Newtonian flow behavior with cP 10.633 ± 0.603 (mPa⋅s). A steady drug release and linear permeation profiles were observed and showed a 90% permeation rate from the released drug. Ibuprofen microemulsion showed excellent stability in 3-months accelerated storage conditions, heating-cooling and freeze-thaw cycles, accelerated centrifugation, and 6- and 12-months long-term storage conditions. In vivo studies in rats further demonstrated a 4-fold higher brain uptake of ibuprofen from the microemulsion compared to the reference solution and nearly 4-fold and 10-fold higher compared to the intravenous and oral administrations. This study provides an exciting repurposing strategy and new administration route for the treatment of Alzheimer's disease.

PMID:34121565 | DOI:10.1080/10717544.2021.1937383

J Biomed Inform. 2021 Jun 10:103838. doi: 10.1016/j.jbi.2021.103838. Online ahead of print.

ABSTRACT

We aimed to develop and validate a new graph embedding algorithm for embedding drug-disease-target networks to generate novel drug repurposing hypotheses. Our model denotes drugs, diseases and targets as subjects, predicates and objects, respectively. Each entity is represented by a multidimensional vector and the predicate is regarded as a translation vector from a subject to an object vectors. These vectors are optimized so that when a subject-predicate-object triple represents a known drug-disease-target relationship, the summed vector between the subject and the predicate is to be close to that of the object; otherwise, the summed vector is distant from the object. The DTINet dataset was utilized to test this algorithm and discover unknown links between drugs and diseases. In cross-validation experiments, this new algorithm outperformed the original DTINet model. The MRR (Mean Reciprocal Rank) values of our models were around 0.80 while those of the original model were about 0.70. In addition, we have identified and verified several pairs of new therapeutic relations as well as adverse effect relations that were not recorded in the original DTINet dataset. This approach showed excellent performance, and the predicted drug-disease and drug-side-effect relationships were found to be consistent with literature reports. This novel method can be used to analyze diverse types of emerging biomedical and healthcare-related knowledge graphs (KG).

PMID:34119691 | DOI:10.1016/j.jbi.2021.103838

J Infect Public Health. 2021 May 26;14(7):852-862. doi: 10.1016/j.jiph.2021.05.009. Online ahead of print.

ABSTRACT

The ongoing enormous loss of human life owing to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has led to a global crisis ranging from the collapse of health - care systems to socio-economic instability. As SARS-CoV-2 is a novel virus, very little information is available from researchers and therefore, a rigorous effort is required to decode its pathogenicity. There are no licenced treatment options available for treating SARS-CoV-2 infections and the development of a new antiviral drug targeting coronavirus cannot happen soon. Consequently, drug repurposing is a promising solution for combating the present pandemic. In this review, we have thoroughly discussed all the proteins encoded by the SARS-CoV-2 genome; their importance in pathogenicity and their potential role in drug discovery. Also, the budding threat of co-infections by other pathogenic microbes has been highlighted. Furthermore, the advances made in the medicinal field for the treatment and prevention of this viral infection is explained. Altogether, this review will provide some insightful discussions about this infectious disease and will meet certain of the knowledge gaps which exist by presenting an exhaustive and extensive scientific report on the ongoing mission for COVID-19 drug discovery.

PMID:34118735 | DOI:10.1016/j.jiph.2021.05.009

Cardiovasc Res. 2021 Jun 12:cvab202. doi: 10.1093/cvr/cvab202. Online ahead of print.

ABSTRACT

AIMS: Interleukin-1β (IL-1β) is an important pathogenic factor in cardiovascular diseases including chronic heart failure (HF). The CANTOS trial highlighted that inflammasomes as primary sources of IL-1 β are promising new therapeutic targets in cardiovascular diseases. Therefore, we aimed to assess inflammasome activation in failing hearts to identify activation patterns of inflammasome subtypes as sources of IL-1β.

METHODS AND RESULTS: Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human heart failure regardless of the etiology (ischemic or dilated cardiomyopathy) while the NLRP1/NALP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change in HF samples. AIM2 expression was primarily detected in monocytes/macrophages of failing hearts. Translational animal models of HF (pressure or volume overload, and permanent coronary artery ligation in rat, as well as ischemia/reperfusion-induced HF in pigs) demonstrated activation pattern of AIM2 similar to that of observed in end-stages of human HF. In vitro AIM2 inflammasome activation in human THP-1 monocytic cells and human AC16 cells was significantly reduced by pharmacological blockade of pannexin-1 channels by the clinically used uricosuric drug probenecid. Probenecid was also able to reduce pressure overload-induced mortality and restore indices of disease severity in a rat chronic HF model in vivo.

CONCLUSIONS: This is the first report showing that AIM2 and NLRC4 inflammasome activation contribute to chronic inflammation in heart failure and that probenecid alleviates chronic HF by reducing inflammasome activation. The present translational study suggests the possibility of repositioning of probenecid for HF indications.

PMID:34117866 | DOI:10.1093/cvr/cvab202

Sci Rep. 2021 Jun 11;11(1):12338. doi: 10.1038/s41598-021-91428-4.

ABSTRACT

Drug development for rare and intractable diseases has been challenging for decades due to the low prevalence and insufficient information on these diseases. Drug repositioning is increasingly being used as a promising option in drug development. We aimed to analyze the trend of drug repositioning and inter-disease drug repositionability among rare and intractable diseases. We created a list of rare and intractable diseases based on the designated diseases in Japan. Drug information extracted from clinical trial data were integrated with information of drug target genes, which represent the mechanism of drug action. We obtained 753 drugs and 551 drug target genes from 8307 clinical trials for 189 diseases or disease groups. Trend analysis of drug sharing between a disease pair revealed that 1676 drug repositioning events occurred in 4401 disease pairs. A score, Rgene, was invented to investigate the proportion of drug target genes shared between a disease pair. Annual changes of Rgene corresponded to the trend of drug repositioning and predicted drug repositioning events occurring within a year or two. Drug target gene-based analyses well visualized the drug repositioning landscape. This approach facilitates drug development for rare and intractable diseases.

PMID:34117295 | DOI:10.1038/s41598-021-91428-4

Comput Biol Med. 2021 Jun 8;134:104538. doi: 10.1016/j.compbiomed.2021.104538. Online ahead of print.

ABSTRACT

The outbreak of COVID-19 disease caused by SARS-CoV-2, along with the lack of targeted medicaments, forced the scientific world to search for new antiviral formulations. In the current emergent situation, drug repurposing of well-known traditional and/or approved drugs could be the most effective strategy. Herein, through computational approaches, we aimed to screen 14 natural compounds from limonoids and terpenoids class for their ability to inhibit the key therapeutic target proteins of SARS-CoV-2. Among these, some limonoids, namely deacetylnomilin, ichangin and nomilin, and the terpenoid β-amyrin provided good interaction energies with SARS-CoV-2 3CL hydrolase (Mpro) in molecular dynamic simulation. Interestingly, deacetylnomilin and ichangin showed direct interaction with the catalytic dyad of the enzyme so supporting their potential role in preventing SARS-CoV-2 replication and growth. On the contrary, despite the good affinity with the spike protein RBD site, all the selected phytochemicals lose contact with the amino acid residues over the course of 120ns-long molecular dynamics simulations therefore suggesting they scarcely can interfere in SARS-CoV-2 binding to the ACE2 receptor. The in silico analyses of docking score and binding energies, along with predicted pharmacokinetic profiles, indicate that these triterpenoids might have potential as inhibitors of SARS-CoV-2 Mpro, recommending further in vitro and in vivo investigations for a complete understanding and confirmation of their inhibitory potential.

PMID:34116362 | DOI:10.1016/j.compbiomed.2021.104538

ACS Infect Dis. 2021 Jun 11. doi: 10.1021/acsinfecdis.1c00139. Online ahead of print.

ABSTRACT

Leishmaniases are vector-borne neglected diseases caused by single-celled parasites. The search for new antileishmanial drugs has experienced a strong boost thanks to the application of bioimaging to phenotypic screenings based on intracellular amastigotes. Mouse splenic explants infected with fluorescent strains of Leishmania are proven tools of drug discovery, where hits can be easily transferred to preclinical in vivo models. We have developed a two-staged platform for antileishmanial drugs. First, we screened two commercial collections of repurposing drugs with a total of 1769 compounds in ex vivo mouse splenocytes infected with an infrared emitting Leishmania infantum strain. The most active and safest compounds were scaled-up to in vivo models of chronic Leishmania donovani visceral leishmaniasis and Leishmania major cutaneous leishmaniasis. From the total of 1769 compounds, 12 hits with selective indices >35 were identified, and 4 of them were tested in vivo in a model of L. donovani visceral leishmaniasis. Nifuratel, a repurposed synthetic nitrofuran, when administered orally at 50 mg/kg bw once or twice a day for 10 days, caused >80% reduction in the parasitic load. Furthermore, the intralesional administration of nifuratel in a model of cutaneous leishmaniasis by L. major produced the parasitological cure. From the previous results we have deduced the great capacity of mouse splenic explants to identify new hits, a model which could be easily transferred to in vivo models, as well as the potential use of nifuratel as an alternative to the current treatment of cutaneous leishmaniasis.

PMID:34114790 | DOI:10.1021/acsinfecdis.1c00139

Phytother Res. 2021 Jun 11. doi: 10.1002/ptr.7156. Online ahead of print.

ABSTRACT

In the current study, the underlying anti-metastatic mechanism of melatonin contained in some edible plants was explored in association with transmembrane protease serine 4 (TMPRSS4) mediated metastasis and epithelial-mesenchymal transition (EMT) signaling in human HCT15 and SW620 colorectal cancer cells. Here, TMPRSS4 was highly expressed in HCT15, but was weakly expressed in SW620 cells. Melatonin exerted weak cytotoxicity, decreased invasion, adhesion, and migration, and attenuated the expression of TMPRSS4, cyclin E, pro-urokinase-type plasminogen activator (pro-uPA), p-signal transducer and activator of transcription 3 (p-STAT3), p-focal adhesion kinase (p-FAK), Snail and increased the expression of E-cadherin, p27, pp38 and p-Jun N-terminal kinases (p-JNK) in HCT15 cells. Conversely, overexpression of TMPRSS4 reduced the ability of melatonin to activate E-cadherin and reduce Snail. Furthermore, even in SW620 cells transfected with TMPRSS4-overexpression plasmid, melatonin effectively suppressed invasion and migration along with decreased expression of Snail, cyclin A, cyclin E, pro-uPA and p-FAK and increased expression of E-cadherin and p27. Overall, these findings provide evidence that melatonin suppresses metastasis in colon cancer cells via inhibition of TMPRSS4 mediated EMT.

PMID:34114707 | DOI:10.1002/ptr.7156

Chemistry. 2021 Jun 10. doi: 10.1002/chem.202101366. Online ahead of print.

ABSTRACT

We identified the gold(I)-dithiocarbamate (dtc) complex [Au(N,N-diethyl)dtc]2 as the active cytotoxic agent in the combination treatment of sodium aurothiomalate and disulfiram on a panel of cancer cell lines. In addition to demonstrating pronounced differential cytotoxicity to these cell lines, the gold complex showed no cross-resistance in therapy-surviving cancer cells. In the course of a medicinal chemistry campaign on this class of poorly soluble gold(I)-dtc complexes, we synthesized >35 derivatives and used x-ray crystallography to examine structural aspects of the dtc moiety. A group of hydroxy-substituted complexes has an improved solubility profile, and we found that these complexes form 2:1 host-guest inclusion complexes with β-cyclodextrin (CD), exhibiting a rarely observed "tail-to-tail" arrangement of the CD cones. Formulation of a hydroxy-substituted gold(I)-dtc complex with excess sulfobutylether-β-CD prevents the induction of mitochondrial reactive oxygen species, which is a major burden in the development of metallodrugs.

PMID:34114261 | DOI:10.1002/chem.202101366

Sci Rep. 2021 Jun 10;11(1):12310. doi: 10.1038/s41598-021-91625-1.

ABSTRACT

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.

PMID:34112877 | DOI:10.1038/s41598-021-91625-1

J Cheminform. 2021 Jun 10;13(1):44. doi: 10.1186/s13321-021-00523-1.

ABSTRACT

Target prediction is a crucial step in modern drug discovery. However, existing experimental approaches to target prediction are time-consuming and costly. Here, we introduce LigTMap, an online server with a fully automated workflow that can identify protein targets of chemical compounds among 17 classes of therapeutic proteins extracted from the PDBbind database. It combines ligand similarity search with docking and binding similarity analysis to predict putative targets. In the validation experiment of 1251 compounds, targets were successfully predicted for more than 70% of the compounds within the top-10 list. The performance of LigTMap is comparable to the current best servers SwissTargetPrediction and SEA. When testing with our newly compiled compounds from recent literature, we get improved top 10 success rate (66% ours vs. 60% SwissTargetPrediction and 64% SEA) and similar top 1 success rate (45% ours vs. 51% SwissTargetPrediction and 41% SEA). LigTMap directly provides ligand docking structures in PDB format, so that the results are ready for further structural studies in computer-aided drug design and drug repurposing projects. The LigTMap web server is freely accessible at https://cbbio.online/LigTMap . The source code is released on GitHub ( https://github.com/ShirleyWISiu/LigTMap ) under the BSD 3-Clause License to encourage re-use and further developments.

PMID:34112240 | DOI:10.1186/s13321-021-00523-1

Eur J Pharmacol. 2021 Jun 7:174233. doi: 10.1016/j.ejphar.2021.174233. Online ahead of print.

ABSTRACT

Dihydroorotate dehydrogenase (DHODH) is rate-limiting enzyme in biosynthesis of pyrimidone which catalyzes the oxidation of dihydro-orotate to orotate. Orotate is utilized in the biosynthesis of uridine-monophosphate. DHODH inhibitors have shown promise as antiviral agent against Cytomegalovirus, Ebola, Influenza, Epstein Barr and Picornavirus. Anti-SARS-CoV-2 action of DHODH inhibitors are also coming up. In this review, we have reviewed the safety and efficacy of approved DHODH inhibitors (leflunomide and teriflunomide) against COVID-19. In target-centered in silico studies, leflunomide showed favorable binding to active site of MPro and spike: ACE2 interface. In artificial-intelligence/machine-learning based studies, leflunomide was among the top 50 ligands targeting spike: ACE2 interaction. Leflunomide is also found to interact with differentially regulated pathways [identified by KEGG (Kyoto Encyclopedia of Genes and Genomes) and reactome pathway analysis of host transcriptome data] in cogena based drug-repurposing studies. Based on GSEA (gene set enrichment analysis), leflunomide was found to target pathways enriched in COVID-19. In vitro, both leflunomide (EC50 41.49±8.8μmol/L) and teriflunomide (EC50 26μmol/L) showed SARS-CoV-2 inhibition. In clinical studies, leflunomide showed significant benefit in terms of decreasing the duration of viral shredding, duration of hospital stay and severity of infection. However, no advantage was seen while combining leflunomide and IFN alpha-2a among patients with prolonged post symptomatic viral shredding. Common adverse effects of leflunomide were hyperlipidemia, leucopenia, neutropenia and liver-function alteration. Leflunomide/teriflunomide may serve as an agent of importance to achieve faster virological clearance in COVID-19, however, findings needs to be validated in bigger sized placebo controlled studies.

PMID:34111397 | DOI:10.1016/j.ejphar.2021.174233

Front Immunol. 2021 May 24;12:669400. doi: 10.3389/fimmu.2021.669400. eCollection 2021.

ABSTRACT

OBJECTIVE: Development and progression of immune-mediated inflammatory diseases (IMIDs) involve intricate dysregulation of the disease-associated genes (DAGs) and their expressing immune cells. Identifying the crucial disease-associated cells (DACs) in IMIDs has been challenging due to the underlying complex molecular mechanism.

METHODS: Using transcriptome profiles of 40 different immune cells, unsupervised machine learning, and disease-gene networks, we constructed the Disease-gene IMmune cell Expression (DIME) network and identified top DACs and DAGs of 12 phenotypically different IMIDs. We compared the DIME networks of IMIDs to identify common pathways between them. We used the common pathways and publicly available drug-gene network to identify promising drug repurposing targets.

RESULTS: We found CD4+Treg, CD4+Th1, and NK cells as top DACs in inflammatory arthritis such as ankylosing spondylitis (AS), psoriatic arthritis, and rheumatoid arthritis (RA); neutrophils, granulocytes, and BDCA1+CD14+ cells in systemic lupus erythematosus and systemic scleroderma; ILC2, CD4+Th1, CD4+Treg, and NK cells in the inflammatory bowel diseases (IBDs). We identified lymphoid cells (CD4+Th1, CD4+Treg, and NK) and their associated pathways to be important in HLA-B27 type diseases (psoriasis, AS, and IBDs) and in primary-joint-inflammation-based inflammatory arthritis (AS and RA). Based on the common cellular mechanisms, we identified lifitegrast as a potential drug repurposing candidate for Crohn's disease and other IMIDs.

CONCLUSIONS: Existing methods are inadequate in capturing the intricate involvement of the crucial genes and cell types essential to IMIDs. Our approach identified the key DACs, DAGs, common mechanisms between IMIDs, and proposed potential drug repurposing targets using the DIME network. To extend our method to other diseases, we built the DIME tool (https://bitbucket.org/systemsimmunology/dime/) to help scientists uncover the etiology of complex and rare diseases to further drug development by better-determining drug targets, thereby mitigating the risk of failure in late clinical development.

PMID:34108969 | PMC:PMC8181425 | DOI:10.3389/fimmu.2021.669400

J Biol Methods. 2021 May 26;8(2 COVID 19 Spec Iss):e148. doi: 10.14440/jbm.2021.351. eCollection 2021.

ABSTRACT

We describe a procedure of performing in silico (virtual) screening using a web-based service, the MTiOpenScreen, which is freely accessible to non-commercial users. We shall use the SARS-CoV-2 main protease as an example. Starting from a structure downloaded from the Protein Data Bank, we discuss how to prepare the coordinates file, taking into account the known biochemical background information of the target protein. The reader will find that this preparation step takes up most of the effort before the target is ready for screening. The steps for uploading the target structure and defining the search volume by critical residues, and the main parameters to use, are outlined. When this protocol is followed, the user will expect to obtain a ranked list of small approved drug compounds docked into the target structure. The results can be readily examined graphically on the web site or downloaded for studying in a local molecular graphics program such as PyMOL.

PMID:34104664 | PMC:PMC8175336 | DOI:10.14440/jbm.2021.351

medRxiv. 2021 Jun 2:2021.05.31.21254851. doi: 10.1101/2021.05.31.21254851. Preprint.

ABSTRACT

BACKGROUND: Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes and readily available compounds that reduce COVID-19 host susceptibility is a critical next step.

METHODS: We integrate COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX) and perturbargen signatures to identify candidate genes and compounds that reverse the predicted gene expression dysregulation associated with COVID-19 susceptibility. The top candidate gene is validated by testing both its GReX and observed blood transcriptome association with COVID-19 severity, as well as by in vitro perturbation to quantify effects on viral load and molecular pathway dysregulation. We validate the in silico drug repositioning analysis by examining whether the top candidate compounds decrease COVID-19 incidence based on epidemiological evidence.

RESULTS: We identify IL10RB as the top key regulator of COVID-19 host susceptibility. Predicted GReX up-regulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes. In vitro IL10RB overexpression is associated with increased viral load and activation of immune-related molecular pathways. Azathioprine and retinol are prioritized as candidate compounds to reduce the likelihood of testing positive for COVID-19.

CONCLUSIONS: We establish an integrative data-driven approach for gene target prioritization. We identify and validate IL10RB as a suitable molecular target for modulation of COVID-19 host susceptibility. Finally, we provide evidence for a few readily available medications that would warrant further investigation as drug repositioning candidates.

PMID:34100031 | PMC:PMC8183086 | DOI:10.1101/2021.05.31.21254851