On-Label or Off-Label? Overcoming Regulatory and Financial Barriers to Bring Repurposed Medicines to Cancer Patients.

Front Pharmacol. 2019;10:1664

Authors: Verbaanderd C, Rooman I, Meheus L, Huys I

Abstract
Repurposing of medicines has gained a lot of interest from the research community in recent years as it could offer safe, timely, and affordable new treatment options for cancer patients with high unmet needs. Increasingly, questions arise on how new uses will be translated into clinical practice, especially in case of marketed medicinal products that are out of basic patent or regulatory protection. The aim of this study was to portray the regulatory framework relevant for making repurposed medicines available to cancer patients in Europe and propose specific policy recommendations to address the current regulatory and financial barriers. We outlined two routes relevant to the clinical adoption of a repurposed medicine. First, a new indication can be approved, and thus brought on-label, via the marketing authorization procedures established in European and national legislation. Such procedures initiate a detailed and independent assessment of the quality and the benefit-risk balance of a medicinal product in a specific indication, benefiting both prescribers and patients as it reassures them that the scientific evidence is robust. However, the process of marketing authorization for new therapeutic indications entails a high administrative burden and significant costs while the return-on-investment for the pharmaceutical industry is expected to be low or absent for medicines that are out of basic patent and regulatory protection. Moreover, most of the repurposing research is conducted by independent or academic researchers who do not have the expertise or resources to get involved in regulatory procedures. A second option is to prescribe a medicine off-label for the new indication, which is managed at the national level in Europe. While off-label use could provide timely access to treatments for patients with urgent medical needs, it also entails important safety, liability and financial risks for patients, physicians, and society at large. In view of that, we recommend finding solutions to facilitate bringing new uses on-label, for example by developing a collaborative framework between not-for-profit and academic organizations, pharmaceutical industry, health technology assessment bodies, payers, and regulators.

PMID: 32076405 [PubMed]

Time-resolved evaluation of compound repositioning predictions on a text-mined knowledge network.

BMC Bioinformatics. 2019 Dec 11;20(1):653

Authors: Mayers M, Li TS, Queralt-Rosinach N, Su AI

Abstract
BACKGROUND: Computational compound repositioning has the potential for identifying new uses for existing drugs, and new algorithms and data source aggregation strategies provide ever-improving results via in silico metrics. However, even with these advances, the number of compounds successfully repositioned via computational screening remains low. New strategies for algorithm evaluation that more accurately reflect the repositioning potential of a compound could provide a better target for future optimizations.
RESULTS: Using a text-mined database, we applied a previously described network-based computational repositioning algorithm, yielding strong results via cross-validation, averaging 0.95 AUROC on test-set indications. However, to better approximate a real-world scenario, we built a time-resolved evaluation framework. At various time points, we built networks corresponding to prior knowledge for use as a training set, and then predicted on a test set comprised of indications that were subsequently described. This framework showed a marked reduction in performance, peaking in performance metrics with the 1985 network at an AUROC of .797. Examining performance reductions due to removal of specific types of relationships highlighted the importance of drug-drug and disease-disease similarity metrics. Using data from future timepoints, we demonstrate that further acquisition of these kinds of data may help improve computational results.
CONCLUSIONS: Evaluating a repositioning algorithm using indications unknown to input network better tunes its ability to find emerging drug indications, rather than finding those which have been randomly withheld. Focusing efforts on improving algorithmic performance in a time-resolved paradigm may further improve computational repositioning predictions.

PMID: 31829175 [PubMed - indexed for MEDLINE]

Add-on spironolactone as antagonist of the NRG1-ERBB4 signaling pathway for the treatment of schizophrenia: Study design and methodology of a multicenter randomized, placebo-controlled trial.

Contemp Clin Trials Commun. 2020 Mar;17:100537

Authors: Hasan A, Roeh A, Leucht S, Langguth B, Hansbauer M, Oviedo-Salcedo T, Kirchner SK, Papazova I, Löhrs L, Wagner E, Maurus I, Strube W, Rossner MJ, Wehr MC, Bauer I, Heres S, Leucht C, Kreuzer PM, Zimmermann S, Schneider-Axmann T, Görlitz T, Karch S, Egert-Schwender S, Schossow B, Rothe P, Falkai P

Abstract
Background: Preclinical studies recently showed that the mineralocorticoid antagonist spironolactone acts also as an antagonist of the NRG1-ERBB4 signaling pathway and improves schizophrenia-like behaviour in Nrg1 transgenic mouse model. As this signaling pathway is critically linked to the pathophysiology of schizophrenia, especially in the context of working-memory dysfunction, spironolactone may be a novel treatment option for patients with schizophrenia targeting cognitive impairments.
Aims: To evaluate whether spironolactone added to an ongoing antipsychotic treatment improves cognitive functioning in schizophrenia.
Methods: The add-on spironolactone for the treatment of schizophrenia trial (SPIRO-TREAT) is a multicenter randomized, placebo-controlled trial with three arms (spironolactone 100 mg, spironolactone 200 mg and placebo). Schizophrenia patients are treated for three weeks and then followed-up for additional nine weeks. As primary outcome, we investigate changes in working memory before and at the end of the intervention phase. We will randomize 90 patients. Eighty-one patients are intended to reach the primary endpoint measure at the end of the three-week intervention period. Secondary endpoints include other measures of cognition, psychopathology, safety measures and biological measures.
Conclusions: SPIRO-TREAT is the first study evaluating the efficacy of the mineralocorticoid receptor antagonist spironolactone to improve cognitive impairments in schizophrenia patients targeting the NRG1-ERBB4 signaling pathway. With SPIRO-TREAT, we intend to investigate a novel treatment option for cognitive impairments in schizophrenia that goes beyond the established concepts of interfering with dopaminergic neurotransmission as key pathway in schizophrenia treatment.
Clinical trial registration: International Clinical Trials Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=EUCTR2014-001968-35-DE.

PMID: 32072071 [PubMed]

Hedgehog signaling pathway inhibitors: an updated patent review (2015-present).

Expert Opin Ther Pat. 2020 Feb 19;:1-16

Authors: Quaglio D, Infante P, Di Marcotullio L, Botta B, Mori M

Abstract
Introduction: Hedgehog (Hh) signaling plays a pivotal role in tissue development and stemness, and its deregulation is found in many different tumors. Several efforts have been devoted to discovery of Hh inhibitors, including three drugs approved by the Food and Drug Administration (FDA), targeting the upstream receptor smoothened (SMO). However, SMO mutations or SMO-independent Hh pathway activation raise the need for novel Hh inhibitors.Areas covered: This review describes Hh inhibitors with anticancer potential patented in the period 2015-present.Expert opinion: Despite the initial enthusiasm in SMO antagonists, drug-resistant mutations, and SMO-independent Hh activation limited their clinical application. A growing number of therapeutic strategies are currently focusing on downstream Hh effectors (i.e. glioma-associate oncogenes (GLI) proteins) or other signaling pathways related to Hh, in addition to drug repositioning. Given the heterogenic nature of cancers, a terrific clinical impact is expected by multi-targeting approaches able to modulate simultaneously SMO and GLI, and/or additional targets that act as regulators of Hh signaling. It is expected that these alternative strategies might be investigated in clinical trials in the next years against a wide variety of tumor types, and that they provide improved outcomes compared to current SMO antagonists or other single-agent anticancer drugs.

PMID: 32070165 [PubMed - as supplied by publisher]

Repurposing Drugs for Acute Myeloid Leukemia: A Worthy Cause or a Futile Pursuit?

Cancers (Basel). 2020 Feb 13;12(2):

Authors: Wojcicki AV, Kadapakkam M, Frymoyer A, Lacayo N, Chae HD, Sakamoto KM

Abstract
Acute myeloid leukemia (AML) is a clinically and genetically heterogenous malignancy of myeloid progenitor cells that affects patients of all ages. Despite decades of research and improvement in overall outcomes, standard therapy remains ineffective for certain subtypes of AML. Current treatment is intensive and leads to a number of secondary effects with varying results by patient population. Due to the high cost of discovery and an unmet need for new targeted therapies that are well tolerated, alternative drug development strategies have become increasingly attractive. Repurposing existing drugs is one approach to identify new therapies with fewer financial and regulatory hurdles. In this review, we provide an overview of previously U.S. Food and Drug Administration (FDA) approved non-chemotherapy drugs under investigation for the treatment of AML.

PMID: 32069925 [PubMed]

Nanosecond electric pulses rapidly enhance the inactivation of Gram-negative bacteria using Gram-positive antibiotics.

Appl Microbiol Biotechnol. 2020 Mar;104(5):2217-2227

Authors: Vadlamani RA, Dhanabal A, Detwiler DA, Pal R, McCarthy J, Seleem MN, Garner AL

Abstract
Physically disrupting microorganism membranes to enable antibiotics to overcome resistance mechanisms that inhibit or excrete antibiotics has great potential for reducing antibiotic doses and rendering resistance mechanisms inert. We demonstrate the synergistic inactivation of a Gram-positive (Staphylococcus aureus) and two Gram-negative (Escherichia coli and Pseudomonas aeruginosa) bacteria by combining 222 30 kV/cm electric pulses (EPs) or 500 20 kV/cm EPs with 300-ns EP duration with various antibiotics with different mechanisms of action is demonstrated. Doses of antibiotics that produced no inactivation in 10 min of exposure in solution with bacteria induced several log reductions under the influence of nanosecond EPs. Combining 2 μg/L or 20 μg/mL of rifampicin with the 30 kV/cm EPs enhanced Staphylococcus aureus inactivation compared with EPs alone, while only a few of the other combinations demonstrated improvement. Combining 2 μg/L or 20 μg/mL of mupirocin or rifampicin with either EP train enhanced E. coli inactivation compared with EPs alone. Combining 2 μg/L or 20 μg/mL of erythromycin or vancomycin with the 30 kV/cm EPs enhanced E. coli inactivation compared with EPs alone. These results indicate that EPs can make Gram-positive antibiotics efficient for inactivating Gram-negative bacteria with future studies required to optimize EP parameters for other antibiotics and Gram-negative bacteria.

PMID: 31965221 [PubMed - indexed for MEDLINE]

Repurposing of Existing Statin Drugs for Treatment of Microbial Infections: How Much Promising?

Infect Disord Drug Targets. 2019;19(3):224-237

Authors: Rana R, Sharma R, Kumar A

Abstract
Today's microbial infections' resistance to approved drugs, the emergence of new infectious diseases and lack of vaccines, create a huge threat to human health. Thus, there is an urgent need to create novel antimicrobial agents, but the high cost and prolonged timeline of novel drug discovery and development is the major barrier to make new drugs. Therefore, there is a need for specific cost effective approaches in order to identify new drugs for the treatment of various microbial infections. Drug repurposition is an alternative technique to find existing clinically approved drugs for other indications. This approach may enhance the portfolio of Pharmaceutical companies by reducing the time and money required for the development of new chemical entity. In literature, various studies have reported some encouraging results regarding the antimicrobial use of existing statin drugs. Further, some clinical studies have also shown the protective effect of statin drugs in reduction of the morbidity and mortality due to many infectious diseases but complete understanding is still lacking. Thus, there is a need for better understanding of the use of statin drugs, especially in the context of antimicrobial effects. In this review, we try to summarize the use of statin drugs in various infectious diseases and their proposed antimicrobial mechanism of action. Further, current challenges and future perspectives of repurposition of statin drugs as antimicrobial agents have also been discussed.

PMID: 30081793 [PubMed - indexed for MEDLINE]

Repurposing the antimalarial pyronaridine tetraphosphate to protect against Ebola virus infection.

PLoS Negl Trop Dis. 2019 11;13(11):e0007890

Authors: Lane TR, Massey C, Comer JE, Anantpadma M, Freundlich JS, Davey RA, Madrid PB, Ekins S

Abstract
Recent outbreaks of the Ebola virus (EBOV) have focused attention on the dire need for antivirals to treat these patients. We identified pyronaridine tetraphosphate as a potential candidate as it is an approved drug in the European Union which is currently used in combination with artesunate as a treatment for malaria (EC50 between 420 nM-1.14 μM against EBOV in HeLa cells). Range-finding studies in mice directed us to a single 75 mg/kg i.p. dose 1 hr after infection which resulted in 100% survival and statistically significantly reduced viremia at study day 3 from a lethal challenge with mouse-adapted EBOV (maEBOV). Further, an EBOV window study suggested we could dose pyronaridine 2 or 24 hrs post-exposure to result in similar efficacy. Analysis of cytokine and chemokine panels suggests that pyronaridine may act as an immunomodulator during an EBOV infection. Our studies with pyronaridine clearly demonstrate potential utility for its repurposing as an antiviral against EBOV and merits further study in larger animal models with the added benefit of already being used as a treatment against malaria.

PMID: 31751347 [PubMed - indexed for MEDLINE]

The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets.

PLoS Negl Trop Dis. 2019 11;13(11):e0007693

Authors: Whatley KCL, Padalino G, Whiteland H, Geyer KK, Hulme BJ, Chalmers IW, Forde-Thomas J, Ferla S, Brancale A, Hoffmann KF

Abstract
BACKGROUND: Praziquantel represents the frontline chemotherapy used to treat schistosomiasis, a neglected tropical disease (NTD) caused by infection with macro-parasitic blood fluke schistosomes. While this drug is safe, its inability to kill all schistosome lifecycle stages within the human host often requires repeat treatments. This limitation, amongst others, has led to the search for novel anti-schistosome replacement or combinatorial chemotherapies. Here, we describe a repositioning strategy to assess the anthelmintic activity of epigenetic probes/inhibitors obtained from the Structural Genomics Consortium.
METHODOLOGY/PRINCIPLE FINDINGS: Thirty-seven epigenetic probes/inhibitors targeting histone readers, writers and erasers were initially screened against Schistosoma mansoni schistosomula using the high-throughput Roboworm platform. At 10 μM, 14 of these 37 compounds (38%) negatively affected schistosomula motility and phenotype after 72 hours of continuous co-incubation. Subsequent dose-response titrations against schistosomula and adult worms revealed epigenetic probes targeting one reader (NVS-CECR2-1), one writer (LLY-507 and BAY-598) and one eraser (GSK-J4) to be particularly active. As LLY-507/BAY-598 (SMYD2 histone methyltransferase inhibitors) and GSK-J4 (a JMJD3 histone demethylase inhibitor) regulate an epigenetic process (protein methylation) known to be critical for schistosome development, further characterisation of these compounds/putative targets was performed. RNA interference (RNAi) of one putative LLY-507/BAY-598 S. mansoni target (Smp_000700) in adult worms replicated the compound-mediated motility and egg production defects. Furthermore, H3K36me2, a known product catalysed by SMYD2 activity, was also reduced by LLY-507 (25%), BAY-598 (23%) and siSmp_000700 (15%) treatment of adult worms. Oviposition and packaging of vitelline cells into in vitro laid eggs was also significantly affected by GSK-J4 (putative cell permeable prodrug inhibitor of Smp_034000), but not by the related structural analogue GSK-J1 (cell impermeable inhibitor).
CONCLUSION/SIGNIFICANCE: Collectively, these results provide further support for the development of next-generation drugs targeting schistosome epigenetic pathway components. In particular, the progression of histone methylation/demethylation modulators presents a tractable strategy for anti-schistosomal control.

PMID: 31730617 [PubMed - indexed for MEDLINE]

MY-5445, a phosphodiesterase type 5 inhibitor, resensitizes ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer drugs.

Am J Cancer Res. 2020;10(1):164-178

Authors: Wu CP, Lusvarghi S, Tseng PJ, Hsiao SH, Huang YH, Hung TH, Ambudkar SV

Abstract
The overexpression of one or multiple ATP-binding cassette (ABC) transporters such as ABCB1, ABCC1 or ABCG2 in cancer cells often leads to the development of multidrug resistance phenotype and consequent treatment failure. Therefore, these transporters constitute an important target to improve the therapeutic outcome in cancer patients. In this study, we employed a drug repurposing approach to identify MY-5445, a known phosphodiesterase type 5 inhibitor, as a selective modulator of ABCG2. We discovered that by inhibiting the drug transport function of ABCG2, MY-5445 potentiates drug-induced apoptosis in ABCG2-overexpressing multidrug-resistant cancer cells and resensitizes these cells to chemotherapeutic drugs. Our data of MY-5445 stimulating the ATPase activity of ABCG2 and molecular docking analysis of its binding to the substrate-binding pocket of ABCG2 provide additional insight into the manner in which MY-5445 interacts with ABCG2. Furthermore, we found that ABCG2 does not confer resistance to MY-5445 in human cancer cells. Overall, our study revealed an additional action of MY-5445 to resensitize ABCG2-overexpressing multidrug-resistant cancer cells to conventional anticancer drugs, and this should be evaluated in future drug combination trials.

PMID: 32064159 [PubMed]

A Proteotranscriptomic-Based Computational Drug-Repositioning Method for Alzheimer's Disease.

Front Pharmacol. 2019;10:1653

Authors: Lee SY, Song MY, Kim D, Park C, Park DK, Kim DG, Yoo JS, Kim YH

Abstract
Numerous clinical trials of drug candidates for Alzheimer's disease (AD) have failed, and computational drug repositioning approaches using omics data have been proposed as effective alternative approaches to the discovery of drug candidates. However, little multi-omics data is available for AD, due to limited availability of brain tissues. Even if omics data exist, systematic drug repurposing study for AD has suffered from lack of big data, insufficient clinical information, and difficulty in data integration on account of sample heterogeneity derived from poor diagnosis or shortage of qualified post-mortem tissue. In this study, we developed a proteotranscriptomic-based computational drug repositioning method named Drug Repositioning Perturbation Score/Class (DRPS/C) based on inverse associations between disease- and drug-induced gene and protein perturbation patterns, incorporating pharmacogenomic knowledge. We constructed a Drug-induced Gene Perturbation Signature Database (DGPSD) comprised of 61,019 gene signatures perturbed by 1,520 drugs from the Connectivity Map (CMap) and the L1000 CMap. Drugs were classified into three DRPCs (High, Intermediate, and Low) according to DRPSs that were calculated using drug- and disease-induced gene perturbation signatures from DGPSD and The Cancer Genome Atlas (TCGA), respectively. The DRPS/C method was evaluated using the area under the ROC curve, with a prescribed drug list from TCGA as the gold standard. Glioblastoma had the highest AUC. To predict anti-AD drugs, DRPS were calculated using DGPSD and AD-induced gene/protein perturbation signatures generated from RNA-seq, microarray and proteomic datasets in the Synapse database, and the drugs were classified into DRPCs. We predicted 31 potential anti-AD drug candidates commonly belonged to high DRPCs of transcriptomic and proteomic signatures. Of these, four drugs classified into the nervous system group of Anatomical Therapeutic Chemical (ATC) system are voltage-gated sodium channel blockers (bupivacaine, topiramate) and monamine oxidase inhibitors (selegiline, iproniazid), and their mechanism of action was inferred from a potential anti-AD drug perspective. Our approach suggests a shortcut to discover new efficacy of drugs for AD.

PMID: 32063857 [PubMed]

DDAPRED: a computational method for predicting drug repositioning using regularized logistic matrix factorization.

J Mol Model. 2020 Feb 15;26(3):60

Authors: Wang X, Yan R

Abstract
Due to rising development costs and stagnant product outputs of traditional drug discovery methods, drug repositioning, which discovers new indications for existing drugs, has attracted increasing interest. Computational drug repositioning can integrate prioritization information and accelerate time lines even further. However, most existing methods for predicting drug repositioning have low precisions. The present article proposed a new method named DDAPRED (https://github.com/nongdaxiaofeng/DDAPRED) for drug repositioning prediction. The method integrated multiple sources of drug similarity and disease similarity information, and it used the regularized logistic matrix decomposition method to significantly improve the prediction performance. In 5-fold cross-validation, the areas under the receiver operating characteristic curve (AUROC) and the precision-recall curve (AUPRC) of DDAPRED reached 0.932 and 0.438, respectively, exceeding other methods. The present study also analyzed the parameters influencing the model performance and the effect of different drug similarity information in-depth, and it verified the treatment relationship of the top 50 predictions with unknown relationships in the training set, further demonstrating the practicability of our method.

PMID: 32062701 [PubMed - in process]

Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with virus internalization process.

J Antibiot (Tokyo). 2019 10;72(10):759-768

Authors: Tran DH, Sugamata R, Hirose T, Suzuki S, Noguchi Y, Sugawara A, Ito F, Yamamoto T, Kawachi S, Akagawa KS, Ōmura S, Sunazuka T, Ito N, Mimaki M, Suzuki K

Abstract
The pandemic influenza 2009 (A(H1N1)pdm09) virus currently causes seasonal and annual epidemic outbreaks. The widespread use of anti-influenza drugs such as neuraminidase and matrix protein 2 (M2) channel inhibitors has resulted in the emergence of drug-resistant influenza viruses. In this study, we aimed to determine the anti-influenza A(H1N1)pdm09 virus activity of azithromycin, a re-positioned macrolide antibiotic with potential as a new anti-influenza candidate, and to elucidate its underlying mechanisms of action. We performed in vitro and in vivo studies to address this. Our in vitro approaches indicated that progeny virus replication was remarkably inhibited by treating viruses with azithromycin before infection; however, azithromycin administration after infection did not affect this process. We next investigated the steps inhibited by azithromycin during virus invasion. Azithromycin did not affect attachment of viruses onto the cell surface, but blocked internalization into host cells during the early phase of infection. We further demonstrated that azithromycin targeted newly budded progeny virus from the host cells and inactivated their endocytic activity. This unique inhibitory mechanism has not been observed for other anti-influenza drugs, indicating the potential activity of azithromycin before and after influenza virus infection. Considering these in vitro observations, we administered azithromycin intranasally to mice infected with A(H1N1)pdm09 virus. Single intranasal azithromycin treatment successfully reduced viral load in the lungs and relieved hypothermia, which was induced by infection. Our findings indicate the possibility that azithromycin could be an effective macrolide for the treatment of human influenza.

PMID: 31300721 [PubMed - indexed for MEDLINE]

Phosphodiesterase-5 inhibitors: Shedding new light on the darkness of depression?

J Affect Disord. 2020 Mar 01;264:138-149

Authors: Duarte-Silva E, Filho AJMC, Barichello T, Quevedo J, Macedo D, Peixoto C

Abstract
BACKGROUND: Phosphodiesterase-5 inhibitors (PDE5Is) are used to treat erectile dysfunction (ED). Recently, the antidepressant-like effect of PDE5Is was demonstrated in animal models of depression. In clinical settings, PDE5Is were studied only for ED associated depression. Hence, there are no studies evaluating the effects of PDE5Is for the treatment of major depressive disorder (MDD) without ED. In this review article, we aimed to discuss the use of PDE5Is in the context of MDD, highlighting the roles of PDE genes in the development of MDD, the potential mechanisms by which PDE5Is can be beneficial for MDD and the potentials and limitations of PDE5Is repurposing to treat MDD.
METHODS: We used PubMed (MEDLINE) database to collect the studies cited in this review. Papers written in English language regardless the year of publication were selected.
RESULTS: A few preclinical studies support the antidepressant-like activity of PDE5Is. Clinical studies in men with ED and depression suggest that PDE5Is improve depressive symptoms. No clinical studies were conducted in subjects suffering from depression without ED. Antidepressant effect of PDE5Is may be explained by multiple mechanisms including inhibition of brain inflammation and modulation of neuroplasticity.
LIMITATIONS: The low number of preclinical and absence of clinical studies to support the antidepressant effect of PDE5Is.
CONCLUSIONS: No clinical trial was conducted to date evaluating PDE5Is in depressed patients without ED. PDE5Is' anti-inflammatory and neuroplasticity mechanisms may justify the potential antidepressant effect of these drugs. Despite this, clinical trials evaluating their efficacy in depressed patients need to be conducted.

PMID: 32056743 [PubMed - in process]

Transcriptional profiling indicates cAMP-driven reversal of HIV latency in monocytes occurs via transcription factor SP-1.

Virology. 2020 Mar;542:40-53

Authors: Moar P, Sushmita K, Kateriya S, Tandon R

Abstract
Latent HIV reservoir is a major barrier to absolute HIV cure. Studies on latency reversal agents (LRA) have by far focused mainly on CD4+ T-lymphocytes, while myeloid reservoirs remain under-represented despite their persistence and key contribution to HIV pathogenesis. cAMP has been shown to increase HIV-1 transcription in latently-infected monocytes/macrophages. In this communication, we explored the potential of commercially available pharmacological drugs and phosphodiesterase inhibitors to reactivate HIV in latently-infected monocytic cell-line, U1. We showed that increased levels of intracellular cAMP reverse HIV latency in vitro, which is specific to cells of the myeloid lineage. High throughput RNA-seq analysis revealed that cAMP modulates transcriptional profile of latently HIV-infected cells and provides favourable cellular environment for HIV to produce viral proteins. This reactivation of latent HIV was inhibited by Mithramycin A, a selective Sp1 inhibitor, indicating that the reversal of HIV latency in monocytes is driven by transcription factor Sp1.

PMID: 32056667 [PubMed - in process]

Exploration of databases and methods supporting drug repurposing: a comprehensive survey.

Brief Bioinform. 2020 Feb 14;:

Authors: Tanoli Z, Seemab U, Scherer A, Wennerberg K, Tang J, Vähä-Koskela M

Abstract
Drug development involves a deep understanding of the mechanisms of action and possible side effects of each drug, and sometimes results in the identification of new and unexpected uses for drugs, termed as drug repurposing. Both in case of serendipitous observations and systematic mechanistic explorations, confirmation of new indications for a drug requires hypothesis building around relevant drug-related data, such as molecular targets involved, and patient and cellular responses. These datasets are available in public repositories, but apart from sifting through the sheer amount of data imposing computational bottleneck, a major challenge is the difficulty in selecting which databases to use from an increasingly large number of available databases. The database selection is made harder by the lack of an overview of the types of data offered in each database. In order to alleviate these problems and to guide the end user through the drug repurposing efforts, we provide here a survey of 102 of the most promising and drug-relevant databases reported to date. We summarize the target coverage and types of data available in each database and provide several examples of how multi-database exploration can facilitate drug repurposing.

PMID: 32055842 [PubMed - as supplied by publisher]

A review of computational drug repurposing.

Transl Clin Pharmacol. 2019 Jun;27(2):59-63

Authors: Park K

Abstract
Although sciences and technology have progressed rapidly, de novo drug development has been a costly and time-consuming process over the past decades. In view of these circumstances, 'drug repurposing' (or 'drug repositioning') has appeared as an alternative tool to accelerate drug development process by seeking new indications for already approved drugs rather than discovering de novo drug compounds, nowadays accounting for 30% of newly marked drugs in the U.S. In the meantime, the explosive and large-scale growth of molecular, genomic and phenotypic data of pharmacological compounds is enabling the development of new area of drug repurposing called computational drug repurposing. This review provides an overview of recent progress in the area of computational drug repurposing. First, it summarizes available repositioning strategies, followed by computational methods commonly used. Then, it describes validation techniques for repurposing studies. Finally, it concludes by discussing the remaining challenges in computational repurposing.

PMID: 32055582 [PubMed]

Computational discovery of therapeutic candidates for preventing preterm birth.

JCI Insight. 2020 Feb 13;5(3):

Authors: Le BL, Iwatani S, Wong RJ, Stevenson DK, Sirota M

Abstract
Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.

PMID: 32051340 [PubMed - in process]

Old Weapon for New Enemy: Drug Repurposing for Treatment of Newly Emerging Viral Diseases.

Virol Sin. 2020 Feb 11;:

Authors: Guo D

PMID: 32048130 [PubMed - as supplied by publisher]

Predict New Therapeutic Drugs for Hepatocellular Carcinoma Based on Gene Mutation and Expression.

Front Bioeng Biotechnol. 2020;8:8

Authors: Yu L, Xu F, Gao L

Abstract
Hepatocellular carcinoma (HCC) is the fourth most common primary liver tumor and is an important medical problem worldwide. However, the use of current therapies for HCC is no possible to be cured, and despite numerous attempts and clinical trials, there are not so many approved targeted treatments for HCC. So, it is necessary to identify additional treatment strategies to prevent the growth of HCC tumors. We are looking for a systematic drug repositioning bioinformatics method to identify new drug candidates for the treatment of HCC, which considers not only aberrant genomic information, but also the changes of transcriptional landscapes. First, we screen the collection of HCC feature genes, i.e., kernel genes, which frequently mutated in most samples of HCC based on human mutation data. Then, the gene expression data of HCC in TCGA are combined to classify the kernel genes of HCC. Finally, the therapeutic score (TS) of each drug is calculated based on the kolmogorov-smirnov statistical method. Using this strategy, we identify five drugs that associated with HCC, including three drugs that could treat HCC and two drugs that might have side-effect on HCC. In addition, we also make Connectivity Map (CMap) profiles similarity analysis and KEGG enrichment analysis on drug targets. All these findings suggest that our approach is effective for accurate predicting novel therapeutic options for HCC and easily to be extended to other tumors.

PMID: 32047745 [PubMed]