Repurposed FDA-approved drugs targeting genes influencing aging can extend lifespan and healthspan in rotifers.

Biogerontology. 2018 04;19(2):145-157

Authors: Snell TW, Johnston RK, Matthews AB, Zhou H, Gao M, Skolnick J

Abstract
Pharmaceutical interventions can slow aging in animals, and have advantages because their dose can be tightly regulated and the timing of the intervention can be closely controlled. They also may complement environmental interventions like caloric restriction by acting additively. A fertile source for therapies slowing aging is FDA approved drugs whose safety has been investigated. Because drugs bind to several protein targets, they cause multiple effects, many of which have not been characterized. It is possible that some of the side effects of drugs prescribed for one therapy may have benefits in retarding aging. We used computationally guided drug screening for prioritizing drug targets to produce a short list of candidate compounds for in vivo testing. We applied the virtual ligand screening approach FINDSITEcomb for screening potential anti-aging protein targets against FDA approved drugs listed in DrugBank. A short list of 31 promising compounds was screened using a multi-tiered approach with rotifers as an animal model of aging. Primary and secondary survival screens and cohort life table experiments identified four drugs capable of extending rotifer lifespan by 8-42%. Exposures to 1 µM erythromycin, 5 µM carglumic acid, 3 µM capecitabine, and 1 µM ivermectin, extended rotifer lifespan without significant effect on reproduction. Some drugs also extended healthspan, as estimated by mitochondria activity and mobility (swimming speed). Our most promising result is that rotifer lifespan was extended by 7-8.9% even when treatment was started in middle age.

PMID: 29340835 [PubMed - indexed for MEDLINE]

In vitro schistosomicidal activity of tamoxifen and its effectiveness in a murine model of schistosomiasis at a single dose.

Parasitol Res. 2019 Feb 24;:

Authors: Oliveira RN, Corrêa SAP, Vieira KM, Mendes T, Allegretti SM, Miguel DC

Abstract
Schistosomiasis is a neglected tropical disease affecting 220 million people worldwide. Praziquantel has proven to be effective against this parasitic disease, though there are increasing concerns regarding tolerance/resistance that calls for new drugs. Repurposing already existing and well-known drugs has been a desirable approach since it reduces time, costs, and ethical concerns. The anti-cancer drug tamoxifen (TAM) has been used worldwide for several decades to treat and prevent breast cancer. Previous reports stated that TAM affects Schistosoma hormonal physiology; however, no controlled schistosomicidal in vivo assays have been conducted. In this work, we evaluated the effect of TAM on female and male Schistosoma mansoni morphology, motility, and egg production. We further assessed worm survival and egg production in S. mansoni-infected mice. TAM induced morphological alterations in male and female parasites, as well as in eggs in vitro. Furthermore, in our in vivo experiments, one single dose of intraperitoneal TAM citrate reduced the total worm burden by 73% and led to a decrease in the amount of eggs in feces and low percentages of immature eggs in the small intestine wall. Eggs obtained from TAM citrate-treated mice were reduced in size and presented hyper-vacuolated structures. Our results suggest that TAM may be repurposed as a therapeutic alternative against S. mansoni infections.

PMID: 30798369 [PubMed - as supplied by publisher]

Drug repurposing for new, efficient, broad spectrum antivirals.

Virus Res. 2019 Feb 19;:

Authors: García-Serradilla M, Risco C, Pacheco B

Abstract
Emerging viruses are a major threat to human health. Recent outbreaks have emphasized the urgent need for new antiviral treatments. For several pathogenic viruses, considerable efforts have focused on vaccine development. However, during epidemics infected individuals need to be treated urgently. High-throughput screening of clinically tested compounds provides a rapid means to identify undiscovered, antiviral functions for well-characterized therapeutics. Repurposed drugs can bypass part of the early cost and time needed for validation and authorization. In this review we describe recent efforts to find broad spectrum antivirals through drug repurposing. We have chosen several candidates and propose strategies to understand their mechanism of action and to determine how resistance to antivirals develops in infected cells.

PMID: 30794895 [PubMed - as supplied by publisher]

NRLMFβ: Beta-distribution-rescored neighborhood regularized logistic matrix factorization for improving the performance of drug-target interaction prediction.

Biochem Biophys Rep. 2019 Jul;18:100615

Authors: Ban T, Ohue M, Akiyama Y

Abstract
Techniques for predicting interactions between a drug and a target (protein) are useful for strategic drug repositioning. Neighborhood regularized logistic matrix factorization (NRLMF) is one of the state-of-the-art drug-target interaction prediction methods; it is based on a statistical model using the Bernoulli distribution. However, the prediction is not accurate when drug-target interaction pairs have less interaction information (e.g., the sum of the number of ligands for a target and the number of target proteins for a drug). This study aimed to address this issue by proposing NRLMF with beta distribution rescoring (NRLMFβ), which is an algorithm to improve the score of NRLMF. The score of NRLMFβ is equivalent to the value of the original NRLMF score when the concentration of the beta distribution becomes infinity. The beta distribution is known as a conjugative prior distribution of the Bernoulli distribution and can reflect the amount of interaction information to its shape based on Bayesian inference. Therefore, in NRLMFβ, the beta distribution was used for rescoring the NRLMF score. In the evaluation experiment, we measured the average values of area under the receiver operating characteristics and area under precision versus recall and the 95% confidence intervals. The performance of NRLMFβ was found to be better than that of NRLMF in the four types of benchmark datasets. Thus, we concluded that NRLMFβ improved the prediction accuracy of NRLMF. The source code is available at https://github.com/akiyamalab/NRLMFb.

PMID: 30793050 [PubMed]

The impact of estimated tumour purity on gene expression-based drug repositioning of Clear Cell Renal Cell Carcinoma samples.

Sci Rep. 2019 Feb 21;9(1):2495

Authors: Koudijs KKM, Terwisscha van Scheltinga AGT, Böhringer S, Schimmel KJM, Guchelaar HJ

Abstract
To find new potentially therapeutic drugs against clear cell Renal Cell Carcinoma (ccRCC), within drugs currently prescribed for other diseases (drug repositioning), we previously searched for drugs which are expected to bring the gene expression of 500 + ccRCC samples from The Cancer Genome Atlas closer to that of healthy kidney tissue samples. An inherent limitation of this bulk RNA-seq data is that tumour samples consist of a varying mixture of cancerous and non-cancerous cells, which influences differential gene expression analyses. Here, we investigate whether the drug repositioning candidates are expected to target the genes dysregulated in ccRCC cells by studying the association with tumour purity. When all ccRCC samples are analysed together, the drug repositioning potential of identified drugs start decreasing above 80% estimated tumour purity. Because ccRCC is a highly vascular tumour, attributed to frequent loss of VHL function and subsequent activation of Hypoxia-Inducible Factor (HIF), we stratified the samples by observed activation of the HIF-pathway. After stratification, the association between estimated tumour purity and drug repositioning potential disappears for HIF-activated samples. This result suggests that the identified drug repositioning candidates specifically target the genes expressed by HIF-activated ccRCC tumour cells, instead of genes expressed by other cell types part of the tumour micro-environment.

PMID: 30792476 [PubMed - in process]

Can anti-obesity drugs be repurposed to treat cocaine addiction?

Neuropsychopharmacology. 2018 09;43(10):1983-1984

Authors: Reiner DJ, Bossert JM

PMID: 29695782 [PubMed - indexed for MEDLINE]

Multi-functional Chimeric Peptides: The More the Merrier.

Protein Pept Lett. 2018;25(12):1090-1100

Authors: Singh A, Srivastava V

Abstract
Peptides are recognized as highly specific and efficacious molecules, thus have found increasing use in developing therapeutics in recent years. It has also been realized that pathophyisology of diseases are very complex and targeting multiple pathways often result in better outcome. The therapeutic potential of a single entity multifunctional peptides that act on two or more distinct receptors with the complementary mechanism of action to gain additive or synergistic benefit compared to monotherapy has been exploited in various disease areas. Herein, we reviewed the therapeutic potential of multifunctional peptides with examples from the field of metabolic, cardiovascular and neuropathic pain disease.

PMID: 30457042 [PubMed - indexed for MEDLINE]

Diverse Chemical Scaffolds Enhance Oligodendrocyte Formation by Inhibiting CYP51, TM7SF2, or EBP.

Cell Chem Biol. 2019 Jan 31;:

Authors: Allimuthu D, Hubler Z, Najm FJ, Tang H, Bederman I, Seibel W, Tesar PJ, Adams DJ

Abstract
Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules. Identification of the cellular targets of these validated hits revealed a majority inhibited the cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP. In addition, evaluation of analogs led to identification of CW3388, a potent EBP-inhibiting enhancer of oligodendrocyte formation poised for further optimization.

PMID: 30773481 [PubMed - as supplied by publisher]

Delivery Systems as Vital Tools in Drug Repurposing.

AAPS PharmSciTech. 2019 Feb 15;20(3):116

Authors: Czech T, Lalani R, Oyewumi MO

Abstract
The process of developing an old drug for new indications is now a widely accepted strategy of shortening drug development time, reducing drug costs, and improving drug availability, especially for rare and neglected diseases. In this mini-review, we highlighted the impact of drug delivery systems in the fulfillment of crucial aspects of drug repurposing such as (i) maximizing the repurposed drug effects on a new target, (ii) minimizing off-target effects, (iii) modulating the release profiles of drug at the site of absorption, (iv) modulating the pharmacokinetics/in vivo biodistribution of the repurposed drug, (v) targeting/modulating drug retention at the sites of action, and (vi) providing a suitable platform for therapeutic application of combination drugs.

PMID: 30771030 [PubMed - in process]

A central hydrophobic E1 region controls the pH range of hepatitis C virus membrane fusion and susceptibility to fusion inhibitors.

J Hepatol. 2019 Feb 12;:

Authors: Banda DH, Perin PM, Brown RJP, Todt D, Solodenko W, Hoffmeyer P, Sahu KK, Houghton M, Meuleman P, Müller R, Kirschning A, Pietschmann T

Abstract
BACKGROUND & AIMS: Hepatitis C virus infection causes chronic liver disease. Antivirals have been developed and cure infection. However, resistance can emerge and salvage therapies with alternative modes of action could be useful. Several licensed drugs have emerged as HCV entry inhibitors representing candidates for drug repurposing. We aimed to dissect their mode of action, identify improved derivatives and determine their viral targets.
METHODS: HCV entry inhibition was tested for a panel of structurally related compounds, using chimeric viruses representing diverse genotypes, in addition to viruses containing previously determined resistance mutations. Chemical modeling and synthesis identified improved derivatives and generation of susceptible and non-susceptible chimeric viruses pinpointed E1 determinants of compound sensitivity.
RESULTS: Molecules of the diphenylpiperazines, diphenylpiperidines, phenothiazines, thioxanthenes, and cycloheptenepiperidines chemotypes inhibit HCV infection via interference with membrane fusion. These molecules and a novel p-methoxy-flunarizine derivative with improved efficacy preferentially inhibit genotype 2 viral strains. Viral residues within a central hydrophobic region of E1 (residues 290-312) control susceptibility. Viral features in this region at the same time govern pH-dependence of viral membrane fusion.
CONCLUSIONS: Small molecules from different chemotypes related to flunarizine preferentially inhibit HCV genotype 2 membrane fusion. A hydrophobic region proximal to the putative fusion loop controls sensitivity to these drugs and the pH-range of membrane fusion. An algorithm considering viral features in this region predicts viral sensitivity to membrane fusion inhibitors. Resistance to flunarizine correlates with more relaxed pH requirements for fusion.
LAY SUMMARY: This study describes diverse compounds as HCV membrane fusion inhibitors. It defines viral properties that determine sensitivity to these molecules and thus provides information to identify patients that may benefit from treatment with membrane fusion inhibitors.

PMID: 30769006 [PubMed - as supplied by publisher]

Combination Anthelmintic/Antioxidant Activity Against Schistosoma Mansoni.

Biomolecules. 2019 Feb 05;9(2):

Authors: Gouveia MJ, Brindley PJ, Rinaldi G, Gärtner F, Correia da Costa JM, Vale N

Abstract
Schistosomiasis is a major neglected tropical disease. Treatment for schistosomiasis with praziquantel (PZQ), which is effective against the parasite, by itself is not capable to counteract infection-associated disease lesions including hepatic fibrosis. There is a pressing need for novel therapies. Due to their biological properties, antioxidant biomolecules might be useful in treating and reverting associated pathological sequelae. Here, we investigated a novel therapy approach based on a combination of anthelmintic drugs with antioxidant biomolecules. We used a host-parasite model involving Bioamphalaria glabrata and newly transformed schistosomula (NTS) of Schistosoma mansoni. For in vitro drug screening assays, was selected several antioxidants and evaluated not only antischistosomal activity but also ability to enhance activity of the anthelmintic drugs praziquantel (PZQ) and artesunate (AS). The morphological alterations induced by compounds alone/combined were assessed on daily basis using an inverted and automated microscope to quantify NTS viability by a fluorometric-based method. The findings indicated that not only do some antioxidants improve antischistosomal activity of the two anthelmintics, but they exhibit activity per se, leading to high mortality of NTS post-exposure. The combination index (CI) of PZQ + Mel (CI = 0.80), PZQ + Resv (CI = 0.74), AS + Resv (CI = 0.34), AS + NAC (CI = 0.89), VDT + Flav (CI = 1.03) and VDT + Resv (CI = 1.06) reveal that they display moderate to strong synergism. The combination of compounds with discrete mechanisms of action might provide a valuable adjunct to contribution for treatment of schistosomiasis-associated disease.

PMID: 30764562 [PubMed - in process]

Comparative functional and pharmacological characterization of Sandoz proposed biosimilar adalimumab (GP2017): rationale for extrapolation across indications.

Expert Opin Biol Ther. 2018 08;18(8):921-930

Authors: Kronthaler U, Fritsch C, Hainzl O, Seidl A, da Silva A

Abstract
BACKGROUND: Biosimilars are approved biologics that match reference medicine in quality, safety, and efficacy. The development of Sandoz proposed biosimilar adalimumab (SPBA; GP2017) involved a target-directed, iterative state-of-the-art quality-by-design development program. Here, we describe the functional and pharmacological characterization of SPBA and its proposed mechanism of action in immune-mediated inflammatory diseases.
METHODS: Sensitive in vitro binding and functional characterization studies, and nonclinical evaluations (pharmacokinetics, pharmacodynamics, and safety/toxicology) were performed as part of a stepwise approach to confirm the biosimilarity of SPBA with reference adalimumab.
RESULTS: Matching values were reported for SPBA and reference adalimumab in binding assays involving tumor necrosis factor (TNF)-α, complement 1q and human immune effector cell Fcγ receptor subtypes in cell-based bioassays for Fc receptor function (complement- and antibody-dependent cytotoxicity), and in apoptosis inhibition. Furthermore, SPBA and reference adalimumab were equivalent in terms of membrane TNF binding and induction of reverse signaling. Pharmacokinetics of SPBA and reference adalimumab were comparable in rabbits, and the two biologics were equally effective in a human TNF transgenic mouse model of polyarthritis.
CONCLUSION: SPBA matches reference adalimumab with regards to target binding, functional, pharmacokinetic, and pharmacodynamic properties at the nonclinical level supporting its approval in all indications of the reference adalimumab.

PMID: 29962245 [PubMed - indexed for MEDLINE]

Spironolactone-induced XPB degradation depends on CDK7 kinase and SCFFBXL 18 E3 ligase.

Genes Cells. 2019 Feb 14;:

Authors: Ueda M, Matsuura K, Kawai H, Wakasugi M, Matsunaga T

Abstract
The multi-subunit complex transcription factor IIH (TFIIH) has dual functions in transcriptional initiation and nucleotide excision repair (NER). TFIIH is comprised of two subcomplexes, the core subcomplex (7 subunits) including XPB and XPD helicases and the cyclin-dependent kinase (CDK)-activating kinase (CAK) subcomplex (3 subunits) containing CDK7 kinase. Recently, it has been reported that spironolactone, an anti-aldosterone drug, inhibits cellular NER by inducing proteasomal degradation of XPB and potentiates the cytotoxicity of platinum-based drugs in cancer cells, suggesting possible drug repositioning. In this study, we have tried to uncover the mechanism underlying the chemical-induced XPB destabilization. Based on siRNA library screening and subsequent analyses, we identified SCFFBXL 18 E3 ligase consisting of Skp1, Cul1, F-box protein FBXL18 and Rbx1 responsible for spironolactone-induced XPB polyubiquitination and degradation. In addition, we revealed that CDK7 kinase activity is required for this process. Finally, we found that the Ser90 residue of XPB is essential for the chemical-induced destabilization. These results led us to propose a model that spironolactone may trigger the phosphorylation of XPB at Ser90 by CDK7, which promotes the recognition and polyubiquitination of XPB by SCFFBXL 18 for proteasomal degradation. This article is protected by copyright. All rights reserved.

PMID: 30762924 [PubMed - as supplied by publisher]

Mutation-specific therapies and drug repositioning in cystic fibrosis.

Minerva Pediatr. 2019 Feb 13;:

Authors: Villella VR, Tosco A, Esposito S, Bona G, Raia V, Maiuri L

Abstract
Cystic Fibrosis (CF) is an inherited, prematurely lethal rare disease affecting more than 85,000 people worldwide. CF is caused by more than 2000 loss-of-function mutations in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR). This review summarizes recent advances in the etiological therapies of CF that aim at repairing the functional defect of CFTR by means of CFTR modulators. We will discuss the state of art of the mutation-specific treatments that are designed to target different steps of the CFTR biogenesis perturbed by mutations in CFTR gene. Moreover, we will discuss how drug repositioning, namely the use of drugs already approved for the treatment of other human diseases, may be repurposed in CF patients to circumvent CFTR dysfunction. Finally, we highlight how the combined use of two o more compounds acting on different disease mechanisms is required to achieve clinical benefit in CF population.

PMID: 30761820 [PubMed - as supplied by publisher]

Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures.

Front Immunol. 2019;10:60

Authors: Pizzorno A, Terrier O, Nicolas de Lamballerie C, Julien T, Padey B, Traversier A, Roche M, Hamelin ME, Rhéaume C, Croze S, Escuret V, Poissy J, Lina B, Legras-Lachuer C, Textoris J, Boivin G, Rosa-Calatrava M

Abstract
Influenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials. We exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo, and ex vivo. Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial. This original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed.

PMID: 30761132 [PubMed - in process]

Towards precision medicine for pain: diagnostic biomarkers and repurposed drugs.

Mol Psychiatry. 2019 Feb 12;:

Authors: Niculescu AB, Le-Niculescu H, Levey DF, Roseberry K, Soe KC, Rogers J, Khan F, Jones T, Judd S, McCormick MA, Wessel AR, Williams A, Kurian SM, White FA

Abstract
We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.

PMID: 30755720 [PubMed - as supplied by publisher]

Drug Repurposing for the Treatment of Bacterial and Fungal Infections.

Front Microbiol. 2019;10:41

Authors: Miró-Canturri A, Ayerbe-Algaba R, Smani Y

Abstract
Multidrug-resistant (MDR) pathogens pose a well-recognized global health threat that demands effective solutions; the situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the ten million deaths predicted to occur by 2050 as a result of MDR bacteria. The repurposing of drugs as therapeutic alternatives for infections has recently gained renewed interest. As drugs approved by the United States Food and Drug Administration, information about their pharmacological characteristics in preclinical and clinical trials is available. Therefore, the time and economic costs required to evaluate these drugs for other therapeutic applications, such as the treatment of bacterial and fungal infections, are mitigated. The goal of this review is to provide an overview of the scientific evidence on potential non-antimicrobial drugs targeting bacteria and fungi. In particular, we aim to: (i) list the approved drugs identified in drug screens as potential alternative treatments for infections caused by MDR pathogens; (ii) review their mechanisms of action against bacteria and fungi; and (iii) summarize the outcome of preclinical and clinical trials investigating approved drugs that target these pathogens.

PMID: 30745898 [PubMed]

p53 Is a Master Regulator of Proteostasis in SMARCB1-Deficient Malignant Rhabdoid Tumors.

Cancer Cell. 2019 Feb 11;35(2):204-220.e9

Authors: Carugo A, Minelli R, Sapio L, Soeung M, Carbone F, Robinson FS, Tepper J, Chen Z, Lovisa S, Svelto M, Amin S, Srinivasan S, Del Poggetto E, Loponte S, Puca F, Dey P, Malouf GG, Su X, Li L, Lopez-Terrada D, Rakheja D, Lazar AJ, Netto GJ, Rao P, Sgambato A, Maitra A, Tripathi DN, Walker CL, Karam JA, Heffernan TP, Viale A, Roberts CWM, Msaouel P, Tannir NM, Draetta GF, Genovese G

Abstract
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.

PMID: 30753823 [PubMed - in process]

From patient-specific induced pluripotent stem cells to clinical translation in long QT syndrome Type 2.

Eur Heart J. 2019 Feb 06;:

Authors: Schwartz PJ, Gnecchi M, Dagradi F, Castelletti S, Parati G, Spazzolini C, Sala L, Crotti L

Abstract
Aims: Having shown that Lumacaftor rescued the hERG trafficking defect in the induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two LQT2 patients, we tested whether the commercial association Lumacaftor + Ivacaftor (LUM + IVA) could shorten the QTc in the same two patients.
Methods and results: After hospital admission and 1 day of baseline recordings, half dose LUM + IVA was administered on Day 1, followed by full dose (LUM 800 mg + IVA 500 mg) for 7 days. A continuous 12-lead Holter ECG allowed a large number of blind QTc measurements. Lumacaftor + Ivacaftor shortened QTc significantly in both patients: in V6 from 551 ± 22 ms to 523 ± 35 ms in Patient 1 (Pt1) and from 472 ± 21 ms to 449 ± 20 ms in Patient 2 (Pt2); in DII from 562 ± 25 ms to 549 ± 35 ms in Pt1 and from 485 ± 32 ms to 452 ± 18 ms in Pt2. In both patients, the percentage of QTc values in the lower tertile increased strikingly: in V6 from 33% to 68% and from 33% to 76%; in DII from 33% to 50% and from 33% to 87%. In the wash-out period a rebound in QTc was observed. On treatment, both patients developed diarrhoea, Pt1 more than Pt2.
Conclusion: This represents the first attempt to validate in patients the in vitro results of a drug repurposing strategy for cardiovascular disorders. Lumacaftor + Ivacaftor shortened significantly the QTc in the two LQT2 patients with a trafficking defect, largely confirming the findings in their iPSC-CMs but with smaller quantitative changes. The findings are encouraging but immediate translation into clinical practice, without validation in more patients, would be premature.

PMID: 30753398 [PubMed - as supplied by publisher]

In silico drug repositioning based on drug-miRNA associations.

Brief Bioinform. 2019 Feb 11;:

Authors: Zhou X, Dai E, Song Q, Ma X, Meng Q, Jiang Y, Jiang W

Abstract
Drug repositioning has become a prevailing tactic as this strategy is efficient, economical and low risk for drug discovery. Meanwhile, recent studies have confirmed that small-molecule drugs can modulate the expression of disease-related miRNAs, which indicates that miRNAs are promising therapeutic targets for complex diseases. In this study, we put forward and verified the hypothesis that drugs with similar miRNA profiles may share similar therapeutic properties. Furthermore, a comprehensive drug-drug interaction network was constructed based on curated drug-miRNA associations. Through random network comparison, topological structure analysis and network module extraction, we found that the closely linked drugs in the network tend to treat the same diseases. Additionally, the curated drug-disease relationships (from the CTD) and random walk with restarts algorithm were utilized on the drug-drug interaction network to identify the potential drugs for a given disease. Both internal validation (leave-one-out cross-validation) and external validation (independent drug-disease data set from the ChEMBL) demonstrated the effectiveness of the proposed approach. Finally, by integrating drug-miRNA and miRNA-disease information, we also explain the modes of action of drugs in the view of miRNA regulation. In summary, our work could determine novel and credible drug indications and offer novel insights and valuable perspectives for drug repositioning.

PMID: 30753359 [PubMed - as supplied by publisher]