Metronomic Chemotherapy for Children in Low- and Middle-Income Countries: Survey of Current Practices and Opinions of Pediatric Oncologists.

J Glob Oncol. 2019 Jul;(5):1-8

Authors: Revon-Rivière G, Banavali S, Heississen L, Gomez Garcia W, Abdolkarimi B, Vaithilingum M, Li CK, Leung PC, Malik P, Pasquier E, Epelman S, Chantada G, André N

Abstract
PURPOSE: Low- and middle-income countries (LMICs) experience the burden of 80% of new childhood cancer cases worldwide, with cure rates as low as 10% in some countries. Metronomics combines frequent administrations of low-dose chemotherapy with drug repurposing, which consists of using already-approved drugs for new medical applications. With wide availability, limited costs, and little infrastructure needs, metronomics can be part of constraint-adapted regimens in these resource-limited settings-with the understanding that metronomics shall not be a substitute for standard treatments when available and doable. Our study aims to describe the experience, practices, opinions, and needs in metronomics of physicians working in LMICs.
METHODS: An online questionnaire was sent to more than 1,200 physicians in pediatric oncology networks in LMICs. Items included the type of center, physician's demographics, experience in pediatric oncology, and experience with current knowledge of metronomics. Opinions and perspectives were explored using multiple-answer and open questions.
RESULTS: Of physicians, 17% responded. Of respondents, 54.9% declared that they had already used a metronomic regimen. The most frequently cited repositioned drugs were celecoxib (44%) followed by propranolol and valproic acid (17%). Respondents highlighted the advantages of outpatient use (20%) and expected low toxicity (24%). In considering the drawbacks of metronomics, 47% of responses highlighted the lack of scientific evidence or guidelines, 33% the availability or affordability of drugs, and 18% the problem of acceptance or compliance. Of physicians, 79% believed that use of metronomics will spread in LMICs in the near future and 98% of them were willing to participate in international metronomic protocols or registries.
CONCLUSION: Metronomics is already used in LMICs and is a potential answer to unmet needs in pediatric oncology. There is room for improvement in the availability of drugs and a necessity to develop collaborative protocols and research to generate level A evidence.

PMID: 31260397 [PubMed - in process]

ANTENNA, a Multi-Rank, Multi-Layered Recommender System for Inferring Reliable Drug-Gene-Disease Associations: Repurposing Diazoxide as a Targeted Anti-Cancer Therapy.

IEEE/ACM Trans Comput Biol Bioinform. 2018 Nov-Dec;15(6):1960-1967

Authors: Wang A, Lim H, Cheng SY, Xie L

Abstract
Existing drug discovery processes follow a reductionist model of "one-drug-one-gene-one-disease," which is inadequate to tackle complex diseases involving multiple malfunctioned genes. The availability of big omics data offers opportunities to transform drug discovery process into a new paradigm of systems pharmacology that focuses on designing drugs to target molecular interaction networks instead of a single gene. Here, we develop a reliable multi-rank, multi-layered recommender system, ANTENNA, to mine large-scale chemical genomics and disease association data for prediction of novel drug-gene-disease associations. ANTENNA integrates a novel tri-factorization based dual-regularized weighted and imputed One Class Collaborative Filtering (OCCF) algorithm, tREMAP, with a statistical framework based on Random Walk with Restart and assess the reliability of specific predictions. In the benchmark, tREMAP clearly outperforms the single-rank OCCF. We apply ANTENNA to a real-world problem: repurposing old drugs for new clinical indications without effective treatments. We discover that FDA-approved drug diazoxide can inhibit multiple kinase genes responsible for many diseases including cancer and kill triple negative breast cancer (TNBC) cells efficiently [Formula: see text]. TNBC is a deadly disease without effective targeted therapies. Our finding demonstrates the power of big data analytics in drug discovery and developing a targeted therapy for TNBC.

PMID: 29993812 [PubMed - indexed for MEDLINE]

Interleukin-18 as a drug repositioning opportunity for inflammatory bowel disease: A Mendelian randomization study.

Sci Rep. 2019 Jun 28;9(1):9386

Authors: Mokry LE, Zhou S, Guo C, Scott RA, Devey L, Langenberg C, Wareham N, Waterworth D, Cardon L, Sanseau P, Davey Smith G, Richards JB

Abstract
Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10-5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

PMID: 31253830 [PubMed - in process]

Identification of a potent benzoxaborole drug candidate for treating cryptosporidiosis.

Nat Commun. 2019 Jun 27;10(1):2816

Authors: Lunde CS, Stebbins EE, Jumani RS, Hasan MM, Miller P, Barlow J, Freund YR, Berry P, Stefanakis R, Gut J, Rosenthal PJ, Love MS, McNamara CW, Easom E, Plattner JJ, Jacobs RT, Huston CD

Abstract
Cryptosporidiosis is a leading cause of life-threatening diarrhea in young children and causes chronic diarrhea in AIDS patients, but the only approved treatment is ineffective in malnourished children and immunocompromised people. We here use a drug repositioning strategy and identify a promising anticryptosporidial drug candidate. Screening a library of benzoxaboroles comprised of analogs to four antiprotozoal chemical scaffolds under pre-clinical development for neglected tropical diseases for Cryptosporidium growth inhibitors identifies the 6-carboxamide benzoxaborole AN7973. AN7973 blocks intracellular parasite development, appears to be parasiticidal, and potently inhibits the two Cryptosporidium species most relevant to human health, C. parvum and C. hominis. It is efficacious in murine models of both acute and established infection, and in a neonatal dairy calf model of cryptosporidiosis. AN7973 also possesses favorable safety, stability, and PK parameters, and therefore, is an exciting drug candidate for treating cryptosporidiosis.

PMID: 31249291 [PubMed - in process]

Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework.

Front Microbiol. 2019;10:1301

Authors: de Oliveira AA, Neves BJ, Silva LDC, Soares CMA, Andrade CH, Pereira M

Abstract
Paracoccidioidomycosis (PCM) is the most prevalent endemic mycosis in Latin America. The disease is caused by fungi of the genus Paracoccidioides and mainly affects low-income rural workers after inhalation of fungal conidia suspended in the air. The current arsenal of chemotherapeutic agents requires long-term administration protocols. In addition, chemotherapy is related to a significantly increased frequency of disease relapse, high toxicity, and incomplete elimination of the fungus. Due to the limitations of current anti-PCM drugs, we developed a computational drug repurposing-chemogenomics approach to identify approved drugs or drug candidates in clinical trials with anti-PCM activity. In contrast to the one-drug-one-target paradigm, our chemogenomics approach attempts to predict interactions between drugs, and Paracoccidioides protein targets. To achieve this goal, we designed a workflow with the following steps: (a) compilation and preparation of Paracoccidioides spp. genome data; (b) identification of orthologous proteins among the isolates; (c) identification of homologous proteins in publicly available drug-target databases; (d) selection of Paracoccidioides essential targets using validated genes from Saccharomyces cerevisiae; (e) homology modeling and molecular docking studies; and (f) experimental validation of selected candidates. We prioritized 14 compounds. Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified.

PMID: 31244810 [PubMed]

Drug Repurposing to Fight Colistin and Carbapenem-Resistant Bacteria.

Front Cell Infect Microbiol. 2019;9:193

Authors: Peyclit L, Baron SA, Rolain JM

Abstract
The emergence of new resistance mechanisms, the failure of classical antibiotics in clinic, the decrease in the development of antibiotics in the industry are all challenges that lead us to consider new strategies for the treatment of infectious diseases. Indeed, in recent years controversy has intensified over strains resistant to carbapenem and/or colistin. Various therapeutic solutions are used to overcome administration of last line antibiotics. In this context, drug repurposing, which consists of using a non-antibiotic compound to treat multi-drug resistant bacteria (MDR), is encouraged. In this review, we first report what may have led to drug repurposing. Main definitions, advantages and drawbacks are summarized. Three major methods are described: phenotypic, computational and serendipity. In a second time we will focus on the current knowledge in drug repurposing for carbapenem and colistin-resistant bacteria with different studies describing repurposed compounds tested on Gram-negative bacteria. Furthermore, we show that drug combination therapies can increase successful by drug repurposing strategy. In conclusion, we discuss the pharmaceutical industries that have little interest in reprofiling drugs due to lack of profits. We also consider what a clinician might think of the indications of these uncommon biologists to treat MDR bacterial infections and avoid therapeutic impasses.

PMID: 31245302 [PubMed - in process]

Identification and in vivo Efficacy Assessment of Approved Orally Bioavailable Human Host Protein-Targeting Drugs With Broad Anti-influenza A Activity.

Front Immunol. 2019;10:1097

Authors: Enkirch T, Sauber S, Anderson DE, Gan ES, Kenanov D, Maurer-Stroh S, von Messling V

Abstract
The high genetic variability of influenza A viruses poses a continual challenge to seasonal and pandemic vaccine development, leaving antiviral drugs as the first line of defense against antigenically different strains or new subtypes. As resistance against drugs targeting viral proteins emerges rapidly, we assessed the antiviral activity of already approved drugs that target cellular proteins involved in the viral life cycle and were orally bioavailable. Out of 15 candidate compounds, four were able to inhibit infection by 10- to 100-fold without causing toxicity, in vitro. Two of the drugs, dextromethorphan and ketotifen, displayed a 50% effective dose between 5 and 50 μM, not only for the classic H1N1 PR8 strain, but also for a pandemic H1N1 and a seasonal H3N2 strain. Efficacy assessment in mice revealed that dextromethorphan consistently resulted in a significant reduction of viral lung titers and also enhanced the efficacy of oseltamivir. Dextromethorphan treatment of ferrets infected with a pandemic H1N1 strain led to a reduction in clinical disease severity, but no effect on viral titer was observed. In addition to identifying dextromethorphan as a potential influenza treatment option, our study illustrates the feasibility of a bioinformatics-driven rational approach for repurposing approved drugs against infectious diseases.

PMID: 31244822 [PubMed - in process]

Computational Drug-repositioning Approach Identifying Sirolimus as a Potential Therapeutic Option for Inflammatory Dilated Cardiomyopathy.

Drug Res (Stuttg). 2019 Jun 25;:

Authors: Shibata K, Endo T, Kuribayashi Y

Abstract
OBJECTIVE: The aim of this study was to determine promising treatment options for human inflammatory dilated cardiomyopathy using a computational drug-repositioning approach (repurposing established drug compounds for new therapeutic indications).
BACKGROUND: If the myocardial tissue is detected to be infiltrated with inflammatory cells, primarily of lymphocytes, and if the virus is confirmed using genetic examination (PCR) or immunostaining, the infection is suspected. However, there is no specific treatment (i. e., an antiviral drug) even if the virus is identified; therefore, we used Connectivity Map to identify compounds showing inverse drug-disease signatures, indicating activity against inflammatory dilated cardiomyopathy.
RESULTS: Potential drug-repositioning candidates for the treatment of inflammatory dilated cardiomyopathy were explored through a systematic comparison of the gene expression profiles induced by drugs using Gene Expression Omnibus and Connectivity Map databases.
CONCLUSION: Using a computational drug-repositioning approach based on the integration of publicly available gene expression signatures of drugs and diseases, sirolimus was suggested as a novel therapeutic option for inflammatory dilated cardiomyopathy.

PMID: 31238376 [PubMed - as supplied by publisher]

Drug repurposing: a promising tool to accelerate the drug discovery process.

Drug Discov Today. 2019 Jun 22;:

Authors: Parvathaneni V, Kulkarni NS, Muth A, Gupta V

Abstract
Traditional drug discovery and development involves several stages for the discovery of a new drug and to obtain marketing approval. It is necessary to discover new strategies for reducing the drug discovery time frame. Today, drug repurposing has gained importance in identifying new therapeutic uses for already-available drugs. Typically, repurposing can be achieved serendipitously (unintentional fortunate observations) or through systematic approaches. Numerous strategies to discover new indications for FDA-approved drugs are discussed in this article. Drug repurposing has therefore become a productive approach for drug discovery because it provides a novel way to explore old drugs for new use but encounters several challenges. Some examples of different approaches are reviewed here.

PMID: 31238113 [PubMed - as supplied by publisher]

Ketamine for Depression, 6: Effects on Suicidal Ideation and Possible Use as Crisis Intervention in Patients at Suicide Risk.

J Clin Psychiatry. 2018 Mar/Apr;79(2):

Authors: Andrade C

Abstract
A growing body of literature suggests that ketamine, administered in subanesthetic doses, has early-onset antidepressant action in patients with severe and even treatment-refractory depression. Many case reports, open-label studies, and randomized controlled trials (RCTs) suggest that ketamine may have dramatic antisuicidal effects, as well. This article examines the benefits of ketamine in patients with suicidal ideation with particular focus on the findings of recent RCTs and meta-analyses. Important findings are that a single dose of ketamine is associated with antisuicidal benefits that emerge within an hour of administration and persist for up to a week. The benefits are seen in patients with mild as well as clinically significant suicidal ideation. The benefits are observed in midazolam- as well as saline-controlled trials. Effect sizes are medium to large. The improvement in suicidal ideation is only partly explained by improvement in depression severity. It is concluded that there is consistent evidence that a single dose of ketamine has dramatic antisuicidal action that emerges almost immediately after dosing and persists for at least a week. The short- and intermediate-term safety and efficacy of ketamine as a crisis intervention treatment for suicidal patients merit study. Areas that need research are outlined.

PMID: 29659211 [PubMed - indexed for MEDLINE]

The Repurposing of Ivermectin for Malaria: A Prospective Pharmacokinetics-Based Virtual Clinical Trials Assessment of Dosing Regimen Options.

J Pharm Sci. 2018 08;107(8):2236-2250

Authors: Badhan R, Zakaria Z, Olafuyi O

Abstract
Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance, attention has turned toward ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiology-based pharmacokinetic model in healthy adults (20-50 years), pediatric (3-5 years/15-25 kg) subjects, and a representative adult malaria population group (Thailand). Dosing optimization demonstrating a twice-daily dose for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and pediatric subjects. Furthermore, to address the occurrence of CYP450 induction that is often encountered with antiretroviral agents, simulated drug-drug interaction studies with efavirenz highlighted that a 1-mg/kg once-daily dose for 5 days would counteract the increased ivermectin hepatic clearance and enable a time above LC50 of 138.8 h in adults and 141.2 h in pediatric subjects. It was also demonstrated that dosage regimen design would require consideration of the age-weight geographical relationship of the subjects, with a dosage regimen for a representative Thailand population group requiring at least a single daily dose for 5 days to maintain ivermectin plasma concentrations and a time above LC50 similar to that in healthy adults.

PMID: 29626533 [PubMed - indexed for MEDLINE]

Nutraceuticals and "Repurposed" Drugs of Phytochemical Origin in Prevention and Interception of Chronic Degenerative Diseases and Cancer.

Curr Med Chem. 2019;26(6):973-987

Authors: Albini A, Bassani B, Baci D, Dallaglio K, Gallazzi M, Corradino P, Bruno A, Noonan DM

Abstract
BACKGROUND: Chronic, degenerative diseases are often characterized by inflammation and aberrant angiogenesis. For these pathologies, including rheumatoid arthritis, cardiovascular and autoimmune diseases, cancer, diabetes, and obesity, current therapies have limited efficacy.
OBJECTIVES: The validation of novel (chemo)preventive and interceptive approaches, and the use of new or repurposed agents, alone or in combination with registered drugs, are urgently required.
RESULTS: Phytochemicals (triterpenoids, flavonoids, retinoids) and their derivatives, nonsteroidal anti-inflammatory drugs (aspirin) as well as biguanides (metformin and phenformin) originally developed from phytochemical backbones, are multi-target agents showing antiangiogenic and anti-anti-inflammatory proprieties. Many of them target AMPK and metabolic pathways such as the mTOR axis. We summarize the beneficial effects of several compounds in conferring protection and supporting therapy, and as a paradigm, we present data on terpenoids & biquanides on beer hop xanthohumol and hydroxytryrosol from olive mill waste waters.
CONCLUSIONS: These molecules could be employed for combinatorial chemoprevention and interception approaches or chemoprevention/therapy regimens for cancer and other chronic complex diseases.

PMID: 28933290 [PubMed - indexed for MEDLINE]

Diphenyleneiodonium chloride (DPIC) displays broad-spectrum bactericidal activity.

Sci Rep. 2017 09 14;7(1):11521

Authors: Pandey M, Singh AK, Thakare R, Talwar S, Karaulia P, Dasgupta A, Chopra S, Pandey AK

Abstract
Indiscriminate use of antibiotics globally has lead to an increase in emergence of drug-resistant pathogens under both nosocomial, as well as more worryingly, in community setting as well. Further, a decrease in the corporate interest and financial commitment has exerted increasing pressure on a rapidly dwindling antimicrobial drug discovery and developmental program. In this context, we have screened the Library of Pharmacologically Active Compounds (LOPAC, Sigma) against Staphylococcus aureus and Mycobacterium tuberculosis to identify potent novel antimicrobial molecules amongst non-antibiotic molecules. Microplate-based whole cell growth assay was performed to analyze the antimicrobial potency of the compounds against Staphylococcus aureus and Mycobacterium tuberculosis. We identified diphenyleneiodonium chloride, a potent inhibitor of NADH/NADPH oxidase, as a broad-spectrum antibiotic potently active against drug resistant strains of Staphylococcus aureus and Mycobacterium tuberculosis. Intriguingly, the diphenyleneiodonium chloride was also very effective against slow-growing non-replicating Mtb persisters. FIC index demonstrated a strongly synergistic interaction between diphenyleneiodonium chloride and Rifampicin while it did not interact with INH. The antimicrobial property of the diphenyleneiodonium chloride was further validated in vivo murine neutropenic thigh S. aureus infection model. Taken together, these findings suggest that Diphenyleneiodonium chloride can be potentially repurposed for the treatment of tuberculosis and staphylococcal infections.

PMID: 28912539 [PubMed - indexed for MEDLINE]

Drug repurposing in alternative medicine: herbal digestive Sochehwan exerts multifaceted effects against metabolic syndrome.

Sci Rep. 2019 Jun 21;9(1):9055

Authors: Lim DW, Kim H, Kim YM, Chin YW, Park WH, Kim JE

Abstract
New drug development is a challenging process that requires high-risk, huge costs and long lead times. Therefore, drug repurposing is considered a strategic and economic way towards successful drug development. Sochehwan (SCH) is a herbal formula well known as a digestive aid in traditional oriental medicine, is referred to in classic medical texts, and is available as an over-the-counter drug for indications of digestive ailments. Interestingly, another medical text written in earlier age describes different indication of SCH yet to be examined. We conducted a series of investigations using maturated adipocytes, free fatty acid (FFA) induced hepatic steatosis model in vitro and high-fat diet (HFD) mice model in vivo. Exposure to SCH regulated expression of adipogenic genes and proteins, significantly inhibiting formation of lipid droplets in 3T3-L1 cells. Similarly, SCH treatment modulated proteins related with energy metabolism decreasing lipid accumulation in FFA induced HepG2 cells. Furthermore, HFD-fed c57BL/6 J mice supplemented with SCH exhibited significant changes in serum glucose and lipid profiles. Histologic analysis of mice liver and adipose tissue showed that SCH administration attenuated hepatic steatosis and hypertrophy of adipose tissue. In overall, the results show that SCH can potentially be used to treat metabolic syndrome (MetS) by enhancing glucose metabolism and inhibiting lipogenesis through activating AMP-activated protein kinase (AMPK) and its downstream signaling. Furthermore, it seems to be a feasible drug repurposing strategy for drugs originating from alternative medicine to revise the value for buried indications of some herbal prescription in old traditional Chinese Medicine (TCM) classics.

PMID: 31227732 [PubMed - in process]

Drug databases and their contributions to drug repurposing.

Genomics. 2019 Jun 18;:

Authors: Masoudi-Sobhanzadeh Y, Omidi Y, Amanlou M, Masoudi-Nejad A

Abstract
Drug repurposing is an interesting field in the drug discovery scope because of reducing time and cost. It is also considered as an appropriate method for finding medications for orphan and rare diseases. Hence, many researchers have proposed novel methods based on databases which contain different information. Thus, a suitable organization of data which facilitates the repurposing applications and provides a tool or a web service can be beneficial. In this review, we categorize drug databases and discuss their advantages and disadvantages. Surprisingly, to the best of our knowledge, the importance and potential of databases in drug repurposing are yet to be emphasized. Indeed, the available databases can be divided into several groups based on data content, and different classes can be applied to find a new application of the existing drugs. Furthermore, we propose some suggestions for making databases more effective and popular in this field.

PMID: 31226485 [PubMed - as supplied by publisher]

Bcl-2/Bcl-xL inhibition predominantly synergistically enhances the anti-neoplastic activity of a low-dose CUSP9 repurposed drug regime against glioblastoma.

Br J Pharmacol. 2019 Jun 21;:

Authors: Halatsch ME, Kast RE, Dwucet A, Hlavac M, Heiland T, Westhoff MA, Debatin KM, Wirtz CR, Siegelin MD, Karpel-Massler G

Abstract
BACKGROUND AND PURPOSE: Drug repurposing represents a promising approach to safely accelerate the clinical application of therapeutics with anti-cancer activity. In this study, we examined whether inhibition of the anti-apoptotic Bcl-2 family proteins Bcl-2 and Bcl-xL enhances the biological effects of the repurposed CUSP9 regimen in an in vitro setting of glioblastoma.
EXPERIMENTAL APPROACH: We applied MTT assays to assess cellular proliferation. Annexin V/PI and TMRE staining were used to examine apoptosis. Western blotting, rtPCR and specific knockdown experiments using siRNA were employed to examine molecular mechanisms of action.
KEY RESULTS: Bcl-2/Bcl-xL inhibition exerted synergistic anti-proliferative effects across established, primary cultured and stem-like glioblastoma cells when combined with CUSP9 which had been reduced to only one tenth of its proposed original concentration (CUSP9-LD). The combination treatment also led to enhanced apoptosis with loss of mitochondrial membrane potential and activation of caspases. On the molecular level, CUSP9-LD counteracted ABT263-mediated upregulation of Mcl-1. Silencing of Mcl-1 enhanced ABT263-mediated apoptosis which indicates that down-regulation of Mcl-1 is crucial for the induction of cell death.
CONCLUSION AND IMPLICATIONS: These data suggest that Bcl-2/Bcl-xL inhibition enhances the susceptibility of glioblastoma cells towards CUSP9, allowing dramatic dose reduction and potentially decreased toxicity when applied clinically. A clinical trial involving the original CUSP doses (CUSP9v3) is currently ongoing in our institution (NCT02770378). The Bcl-2/Bcl-xL inhibitor ABT263 is in clinical trials and might represent a valuable adjunct to the original CUSP.

PMID: 31222722 [PubMed - as supplied by publisher]

Active repurposing of drug candidates for melanoma based on GWAS, PheWAS and a wide range of omics data.

Mol Med. 2019 Jun 20;25(1):30

Authors: Khosravi A, Jayaram B, Goliaei B, Masoudi-Nejad A

Abstract
BACKGROUND: Drug repurposing is a swift, safe, and cheap drug discovery method. Melanoma disorders present low survival and high mortality rates and are challenging to diagnose and treat. Moreover, there is a high volume of worldwide investigations that are attempting to find melanoma-related genes of influence, which can be identified as responsive targets for reliable treatment.
METHOD: In this study, we used a wide range of data analyses to analyze over 1100 genes and proteins of influence with respect to cutaneous malignant melanoma. Our analysis included various investigational results from genome- and phenome-wide association studies (GWAS and PheWAS, respectively), biomedical, transcriptomic, and metabolomic datasets. We then researched the DrugBank for potential melanoma targets from the selected list. We excluded known melanoma targets to obtain a list of druggable proteins. We performed a precise analysis of the drugs' pathogenesis and checked the expression profiles of the selected drugs having high associations with known anti-melanoma drugs.
RESULT: We found 35 drugs that interacted with 20 unique targets. These drugs appear to have high melanoma treatment potentials. We confirmed our results with previous studies and found supporting references for 30 of these drugs. In conclusion, this investigation can be applied to various diseases for the efficient and economical repurposing of various drug compounds. For further validation, the results may be applicable for in vivo tests and clinical trials.

PMID: 31221082 [PubMed - in process]

Amino acid and polyamine membrane transporters in Trypanosoma cruzi: Biological function and evaluation as drug targets.

Curr Med Chem. 2019 Jun 19;:

Authors: Sayé M, Reigada C, Gauna L, Valera-Vera EA, Pereira CA, Miranda MR

Abstract
Amino acids and polyamines are involved in relevant processes for the parasite Trypanosoma cruzi, like protein synthesis, stress resistance, life cycle progression, infection establishment and redox balance, among others. In addition to the biosynthetic routes of amino acids, T. cruzi possesses transport systems that allow the active uptake from the extracellular medium; and in the case of polyamines, the uptake is the unique way to obtain these compounds. The TcAAAP protein family is absent in mammals and its members are responsible for amino acid and derivative uptake, thus the TcAAAP permeases are not only interesting and promising therapeutic targets but also could be used to direct the entry of toxic compounds into the parasite. Although there is a treatment available for Chagas disease, its limited efficacy in the chronic stage of the disease, as well as the side effects reported, highlight the urgent need to develop new therapies. Discovery of new drugs is a slow and money-consuming process, and even during clinical trials the drugs can fail. In this context, drug repositioning is an interesting and recommended strategy by the World Health Organization since costs and time are significantly reduced. In this article, amino acids and polyamines transport and its potential as therapeutic targets will be revised, including examples of synthetic drugs and drug repurposing.

PMID: 31218951 [PubMed - as supplied by publisher]

Signal Transduction Pathways as Therapeutic Target for Chagas Disease.

Curr Med Chem. 2019 Jun 19;:

Authors: Schoijet AC, Sternlieb T, Alonso GD

Abstract
Trypanosomatids are a group of flagellated unicellular eukaryotes, which cause serious human diseases including Chagas disease (Trypanosoma cruzi), sleeping sickness (Trypanosoma brucei spp.) and Leishmaniasis (Leishmania spp.). The second messenger cAMP is involved in numerous and fundamental processes in these parasites including differentiation between stages, proliferation, osmoregulation, oxidative stress and quorum sensing. Interestingly, its signaling pathway is quite different from that of mammals, including structurally different adenylyl cyclases, the shortage of orthologous effector proteins and the absence of G-protein-coupled-receptors, among others. These characteristics make the proteins involved in these transduction pathways good candidates for therapeutic targets. However, the identification of new unknown druggable targets involves extensive research time and is economically very expensive, making the transition from basic research to the clinical phase difficult. Trypanosomatid PDEs have characteristic binding pockets that allow for a differential inhibition from their human orthologs. Modification of human use approved drugs to turn them into trypanocidal treatments could lead to more effective therapies and shorter lab to counter top transition times and lower costs. In view of the fact that kinetoplastid PDEs are highly conserved with their mammalian counterparts, and since there are already numerous drugs on the market against human PDEs, the drug repositioning approach is highly promising. The development of new technologies, higher government and industrial involvement and more scientists committed to basic investigation, are the key to ultimately find an effective treatment and cure for de the neglected tropical diseases.

PMID: 31218950 [PubMed - as supplied by publisher]

Shared Molecular Signatures Across Neurodegenerative Diseases and Herpes Virus Infections Highlights Potential Mechanisms for Maladaptive Innate Immune Responses.

Sci Rep. 2019 Jun 19;9(1):8795

Authors: Costa Sa AC, Madsen H, Brown JR

Abstract
Growing evidence suggests that peripheral factors to the brain driving neuro-inflammation could affect Alzheimer's Disease (AD) and Parkinson's Disease (PD) severity. Herpes simplex virus type 1 (HSV1) infection has been associated with AD while other related viruses, including cytomegalovirus (CMV), Epstein-Bar virus and human herpesvirus 6 (HHV6), are known to infect neurons. Here we compare gene expression profiles between AD or PD patients to those afflicted with herpes viral infections as to discover novel potential neuro-inflammation pathways. We found multiple significant differentially expressed genes (DEGs) shared between AD/PD and viral infections including SESN3 which has a genetic association for increased AD risk. Pathway enrichment analysis revealed viruses shared Oxidative Stress Defense System and LRRK2 pathways with AD and PD, respectively. We further processed our data to identify novel target and drug-repurposing opportunities including anti-inflammatory therapy, immune-modulators and cholinesterase inhibitors which could lead to new therapeutics paradigms for these neurodegenerative diseases.

PMID: 31217489 [PubMed - in process]