Developments on treatment of Chagas disease - from discovery to current times.

Eur Rev Med Pharmacol Sci. 2019 Mar;23(6):2576-2586

Authors: Custodio Leite TO

Abstract
OBJECTIVE: This work aims to collect publications of available drugs for reposition and new substance development against the Chagas disease, since they represent the beginning of a path for new discoveries of viable alternatives to improve the prognosis of millions of patients around the world.
PATIENTS AND METHODS: An extended research on English and Portuguese-language literature in the Scientific Electronic Library Online - Scielo, SciFinder and PubMed - database was made. The bibliography was screened using the keywords "Chagas Disease" and "Treatment".
RESULTS: Despite the low resources available for research and development of drugs against Chagas disease, the knowledge produced in this area is large but not directly proportional to the therapeutic advances. Two categories were analyzed, such as drug repositioning, and new substances were researched.
CONCLUSIONS: Even if great findings were reported, more efforts are necessary to find new therapies against Trypanosoma cruzi (T. cruzi).

PMID: 30964186 [PubMed - in process]

Repurposing Metformin for Cardiovascular Disease.

Circulation. 2018 01 30;137(5):422-424

Authors: Rena G, Lang CC

PMID: 29378754 [PubMed - indexed for MEDLINE]

Potentiation of imatinib by cilostazol in sensitive and resistant gastrointestinal stromal tumor cell lines involves YAP inhibition.

Oncotarget. 2019 Mar 05;10(19):1798-1811

Authors: Vandenberghe P, Delvaux M, Hagué P, Erneux C, Vanderwinden JM

Abstract
Despite the introduction of tyrosine kinase inhibitors, gastrointestinal stromal tumors (GIST) resistance remains a major clinical challenge. We previously identified phosphodiesterase 3A (PDE3A) as a potential therapeutic target expressed in most GIST. The PDE3 inhibitor cilostazol reduced cell viability and synergized with the tyrosine kinase inhibitor imatinib (Gleevec™) in the imatinib-sensitive GIST882 cell line. Here, we found that cilostazol potentiated imatinib also in the imatinib-resistant GIST48 cell line. Cilostazol induced nuclear exclusion, hence inactivation, of the transcriptional co-activator YAP, in a cAMP-independent manner. Verteporfin, a YAP/TEAD interaction inhibitor, reduced by 90% the viability of both GIST882 and GIST48 cells. Our results highlight the potential use of compounds targeting PDE3A or YAP in combined multitherapy to tackle GIST resistance.

PMID: 30956759 [PubMed]

Cheminformatics Tools for Analyzing and Designing Optimized Small-Molecule Collections and Libraries.

Cell Chem Biol. 2019 Mar 12;:

Authors: Moret N, Clark NA, Hafner M, Wang Y, Lounkine E, Medvedovic M, Wang J, Gray N, Jenkins J, Sorger PK

Abstract
Libraries of well-annotated small molecules have many uses in chemical genetics, drug discovery, and therapeutic repurposing. Multiple libraries are available, but few data-driven approaches exist to compare them and design new libraries. We describe an approach to scoring and creating libraries based on binding selectivity, target coverage, and induced cellular phenotypes as well as chemical structure, stage of clinical development, and user preference. The approach, available via the online tool http://www.smallmoleculesuite.org, assembles sets of compounds with the lowest possible off-target overlap. Analysis of six kinase inhibitor libraries using our approach reveals dramatic differences among them and led us to design a new LSP-OptimalKinase library that outperforms existing collections in target coverage and compact size. We also describe a mechanism of action library that optimally covers 1,852 targets in the liganded genome. Our tools facilitate creation, analysis, and updates of both private and public compound collections.

PMID: 30956147 [PubMed - as supplied by publisher]

Development of a validated LC-MS/MS method for the in vitro and in vivo quantitation of sunitinib in glioblastoma cells and cancer patients.

J Pharm Biomed Anal. 2019 Feb 05;164:690-697

Authors: Chatziathanasiadou MV, Stylos EK, Giannopoulou E, Spyridaki MH, Briasoulis E, Kalofonos HP, Crook T, Syed N, Sivolapenko GB, Tzakos AG

Abstract
Sunitinib is a multi-targeted tyrosine kinase inhibitor approved for the treatment of renal cell carcinoma and imatinib-resistant gastrointestinal stromal tumor and is currently being investigated against other forms of malignant tumors. Recently great interest has emerged for the application of sunitinib to glioblastoma treatment. In order to have a method with broad applicability it will be of importance to have access to a method that could be applied both in human plasma and cell uptake studies. No method has been reported thus far for the estimation of sunitinib uptake in glioma cells. We therefore set out to develop a method that could be applied for quantifying sunitinib in human plasma and in cell uptake studies. The method was validated and accredited according to ISO 17025:2005 guideline in human plasma and successfully applied to cancer patient plasma. Also, the method was effectively recruited to establish a protocol for the evaluation of sunitinib accumulation into M095K glioma cells. This method could significantly contribute to developmental phases in repurposing this drug in different cancer types.

PMID: 30472587 [PubMed - indexed for MEDLINE]

Structural and mechanistic insight from antiviral and antiparasitic enzyme drug targets for tropical infectious diseases.

Curr Opin Struct Biol. 2019 Apr 04;59:65-72

Authors: de Godoy AS, Sachetto Fernandes R, Campos Aguiar AC, Vieira Bueno R, de Moraes Roso Mesquita NC, Carvalho Guido RV, Oliva G

Abstract
With almost half of the world population living at risk, tropical infectious diseases cause millions of deaths every year in developing countries. Considering the lack of economic prospects for investment in this field, approaches aiming the rational design of compounds, such as structure-based drug discovery (SBDD), fragment screening, target-based drug discovery, and drug repurposing are of special interest. Herein, we focused in the advances on the field of SBDD targeting arboviruses such as dengue, yellow fever, zika and chikungunya enzymes of the RNA replication complex (RC) and enzymes involved in a variety of pathways essential to ensure parasitic survival in the host, for malaria, Chagas e leishmaniasis diseases. We also highlighted successful examples such as promising new inhibitors and molecules already in preclinical/clinical phase tests, major gaps in the field and perspectives for the future of drug design for tropical diseases.

PMID: 30954758 [PubMed - as supplied by publisher]

Identification of a clinical compound losmapimod that blocks Lassa virus entry.

Antiviral Res. 2019 Apr 03;:

Authors: Zhang X, Yan F, Tang K, Chen Q, Guo J, Zhu W, He S, Banadyga L, Qiu X, Guo Y

Abstract
Lassa virus (LASV) causes Lassa hemorrhagic fever in humans and poses a significant threat to public health in West Africa. Current therapeutic treatments for Lassa fever are limited, making the development of novel countermeasures an urgent priority. In this study, we identified losmapimod, a p38 mitogen-activated protein kinase (MAPK) inhibitor, from 102 screened compounds as an inhibitor of LASV infection. Losmapimod exerted its inhibitory effect against LASV after p38 MAPK down-regulation, and, interestingly, had no effect on other arenaviruses capable of causing viral hemorrhagic fever. Mechanistic studies showed that losmapimod inhibited LASV entry by affecting the stable signal peptide (SSP)-GP2 subunit interface of the LASV glycoprotein, thereby blocking pH-dependent viral fusion. As an aryl heteroaryl bis-carboxyamide derivative, losmapimod represents a novel chemical scaffold with anti-LASV activity, and it provides a new lead structure for the future development of LASV fusion inhibitors.

PMID: 30953674 [PubMed - as supplied by publisher]

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Alterations of the MEK/ERK, BMP, and Wnt/β-catenin pathways detected in the blood of individuals with lymphatic malformations.

PLoS One. 2019;14(4):e0213872

Authors: Kim T, Tafoya E, Chelliah MP, Lekwuttikarn R, Li J, Sarin KY, Teng J

Abstract
Lymphatic malformation (LM) is a developmental anomaly of the lymphatic system that may lead to disfigurement, organ dysfunction and recurrent infection. Though several treatment modalities exist, pharmacotherapy is often associated with side effects and recurrence is common following surgical interventions. Moreover, despite the recent discovery of PIK3CA mutations in lymphatic endothelial cells of LM patients, the full spectrum of molecular pathways involved in LM pathogenesis is poorly understood. Here, we performed RNA sequencing on blood samples obtained from ten LM patients and nine healthy subjects and found 421 differentially expressed genes that stratify LM subjects from healthy controls. Using this LM gene signature, we identified novel pathway alterations in LM, such as oxidative phosphorylation, MEK/ERK, bone morphogenetic protein (BMP), and Wnt/β-catenin pathways, in addition to confirming the known alterations in cell cycle and the PI3K/AKT pathway. Furthermore, we performed computational drug repositioning analysis to predict existing therapies (e.g. sirolimus) and novel classes of drugs for LM. These findings deepen our understanding of LM pathogenesis and may facilitate non-invasive diagnosis, pathway analysis and therapeutic development.

PMID: 30947262 [PubMed - in process]

Repurposing the anthelminthic salicylanilide oxyclozanide against susceptible and clinical resistant Candida albicans strains.

Med Mycol. 2019 Apr 01;57(3):387-390

Authors: Pic E, Burgain A, Sellam A

Abstract
Current antifungal drugs suffer from limitations including toxicity, adverse interactions with other commonly prescribed drugs, and the emergence of resistant strains. Here, we repurposed the anthelmintic oxyclozanide as a potent antifungal agent against both sensitive and resistant clinical isolates of Candida albicans, as well as other human opportunistic fungi. Antifungal activity of oxyclozanide was enhanced when C. albicans grew in nonfermentable carbon sources. Our data support a mechanism of action where oxyclozanide uncoupled the mitochondrial electron transport from oxidative phosphorylation and perturbed the mitochondrial membrane potential.

PMID: 29762783 [PubMed - indexed for MEDLINE]

Drug Repurposing Approaches for the Treatment of Influenza Viral Infection: Reviving Old Drugs to Fight Against a Long-Lived Enemy.

Front Immunol. 2019;10:531

Authors: Pizzorno A, Padey B, Terrier O, Rosa-Calatrava M

Abstract
Influenza viruses still constitute a real public health problem today. To cope with the emergence of new circulating strains, but also the emergence of resistant strains to classic antivirals, it is necessary to develop new antiviral approaches. This review summarizes the state-of-the-art of current antiviral options against influenza infection, with a particular focus on the recent advances of anti-influenza drug repurposing strategies and their potential therapeutic, regulatory and economic benefits. The review will illustrate the multiple ways to reposition molecules for the treatment of influenza, from adventitious discovery to in silico-based screening. These novel antiviral molecules, many of which targeting the host cell, in combination with conventional antiviral agents targeting the virus, will ideally enter the clinics and reinforce the therapeutic arsenal to combat influenza virus infections.

PMID: 30941148 [PubMed - in process]

Carbonyl scavengers as pharmacotherapies in degenerative disease: Hydralazine repurposing and challenges in clinical translation.

Biochem Pharmacol. 2018 08;154:397-406

Authors: Burcham PC

Abstract
During cellular metabolism, spontaneous oxidative damage to unsaturated lipids generates many electrophilic carbonyl compounds that readily attack cell macromolecules, forming adducts that are potential drivers of tissue dysfunction. Since such damage is heightened in many degenerative conditions, researchers have assessed the efficacy of nucleophilic carbonyl-trapping drugs in animal models of such disorders, anticipating that they will protect tissues by intercepting toxic lipid-derived electrophiles (LDEs) within cells. This Commentary explores recent animal evidence for carbonyl scavenger efficacy in two disparate yet significant conditions known to involve LDE production, namely spinal cord injury (SCI) and alcoholic liver disease (ALD). Primary emphasis is placed on studies that utilised hydralazine, a clinically-approved "broad-spectrum" scavenger known to trap multiple LDEs. In addition to reviewing recent studies of hydralazine efficacy in animal SCI and ALD models, the Commentary reviews new insights concerning novel lifespan- and healthspan-extending properties of hydralazine obtained during studies in model invertebrate organisms, since the mechanisms involved seem of likely benefit during the treatment of degenerative disease. Finally, noting that human translation of the histoprotective properties of hydralazine have been limited, the final section of the Commentary will address two obstacles that hamper clinical translation of LDE-trapping therapies while also suggesting potential strategies for overcoming these problems.

PMID: 29883705 [PubMed - indexed for MEDLINE]

Predicting drug-target interaction network using deep learning model.

Comput Biol Chem. 2019 Mar 25;80:90-101

Authors: You J, McLeod RD, Hu P

Abstract
BACKGROUND: Traditional methods for drug discovery are time-consuming and expensive, so efforts are being made to repurpose existing drugs. To find new ways for drug repurposing, many computational approaches have been proposed to predict drug-target interactions (DTIs). However, due to the high-dimensional nature of the data sets extracted from drugs and targets, traditional machine learning approaches, such as logistic regression analysis, cannot analyze these data sets efficiently. To overcome this issue, we propose LASSO (Least absolute shrinkage and selection operator)-based regularized linear classification models and a LASSO-DNN (Deep Neural Network) model based on LASSO feature selection to predict DTIs. These methods are demonstrated for repurposing drugs for breast cancer treatment.
METHODS: We collected drug descriptors, protein sequence data from Drugbank and protein domain information from NCBI. Validated DTIs were downloaded from Drugbank. A new similarity-based approach was developed to build the negative DTIs. We proposed multiple LASSO models to integrate different combinations of feature sets to explore the prediction power and predict DTIs. Furthermore, building on the features extracted from the LASSO models with the best performance, we also introduced a LASSO-DNN model to predict DTIs. The performance of our newly proposed DNN model (LASSO-DNN) was compared with the LASSO, standard logistic (SLG) regression, support vector machine (SVM), and standard DNN models.
RESULTS: Experimental results showed that the LASSO-DNN over performed the SLG, LASSO, SVM and standard DNN models. In particular, the LASSO models with protein tripeptide composition (TC) features and domain features were superior to those that contained other protein information, which may imply that TC and domain information could be better representations of proteins. Furthermore, we showed that the top ranked DTIs predicted using the LASSO-DNN model can potentially be used for repurposing existing drugs for breast cancer based on risk gene information.
CONCLUSIONS: In summary, we demonstrated that the efficient representations of drug and target features are key for building learning models for predicting DTIs. The disease-associated risk genes identified from large-scale genomic studies are the potential drug targets, which can be used for drug repurposing.

PMID: 30939415 [PubMed - as supplied by publisher]

Combined pharmacophore modeling, 3D-QSAR and docking studies to identify novel HDAC inhibitors using drug repurposing.

J Biomol Struct Dyn. 2019 Apr 02;:1-15

Authors: Liu J, Zhu Y, He Y, Zhu H, Gao Y, Li Z, Zhu J, Sun X, Fang F, Wen H, Li W

Abstract
Histone deacetylases (HDACs), a critical family of epigenetic enzymes, has emerged as a promising target for antitumor drugs. Here, we describe our protocol of virtual screening in identification of novel potential HDAC inhibitors through pharmacophore modeling, 3D-QSAR, molecular docking and molecular dynamics (MD) simulation. Considering the limitation of current virtual screening works, drug repurposing strategy was applied to discover druggable HDAC inhibitor. The ligand-based pharmacophore and 3D-QSAR models were established, and their reliability was validated by different methods. Then, the DrugBank database was screened, followed by molecular docking. MD simulation (100 ns) was performed to further study the stability of ligand binding modes. Finally, results indicated the hit DB03889 with high in silico inhibitory potency was suitable for further experimental analysis. Communicated by Ramaswamy H. Sarma.

PMID: 30938574 [PubMed - as supplied by publisher]

In vitro anticancer effect of tricyclic antidepressant nortriptyline on multiple myeloma.

Turk J Biol. 2018;42(5):414-421

Authors: Biber A, Durusu İZ, Özen C

Abstract
Drug repurposing has been proved to be an effective strategy to meet the urgent need for novel anticancer agents for multiple myeloma (MM) treatment. In this work, we aimed to investigate the anticancer effect and mechanism of tricyclic antidepressant nortriptyline (NTP) on the U266 MM cell line. The in vitro inhibitory effect of NTP at various doses and time points was studied. The combination potential of cisplatin-NTP was also investigated. Cell cycle analysis and three flow cytometric apoptosis assays were performed. NTP showed dose- and time-dependent inhibitory effects on the U266 MM cell line. NTP had greater inhibitory effect than cisplatin (IC50 26 µM vs. 40 µM). The cisplatin-NTP combination is antagonistic. In addition to G2/M phase cell cycle arrest, NTP induced apoptosis as indicated by mitochondrial membrane potential and caspase-3 and annexin V assays. NTP has inhibitory and apoptotic effects on U266 MM cells. The cisplatin-NTP combination indicated strong antagonism, which may have significant clinical relevance since antidepressants are commonly employed in adjuvant therapy for cancer patients. Based on these findings, the therapeutic potential of NTP for MM treatment should be investigated with in-depth mechanistic studies and in vivo experiments.

PMID: 30930625 [PubMed]

Repurposing antitubercular agent isoniazid for treatment of prostate cancer.

Biomater Sci. 2018 Dec 18;7(1):296-306

Authors: Lv Q, Wang D, Yang Z, Yang J, Zhang R, Yang X, Wang M, Wang Y

Abstract
The development of versatile antitumor agents with tumor-imaging, targeting and therapeutic activity is promising for clinical cancer therapy. Prostate cancer is still the one of the leading threats to males. Current therapies have restricted clinical efficiency for patients with advanced and metastatic prostate cancer. Recent studies demonstrate that monoamine oxidase A (MAOA) levels elevate with prostate cancer aggression and metastasis. In addition, MAOA inhibitor therapies have been reported as an effective means to reduce the metastasis of prostate cancer and extend mouse survival. Thus, these findings provide evidence that MAOA is promising for the treatment of metastatic and advanced prostate cancer. Herein, three isoniazid (INH)-dye conjugates were synthesized by conjugating MAOA inhibitor INH with mitochondria-targeting NIRF heptamethine dyes to improve the therapeutic efficacy of prostate cancer. These INH-dye conjugates could accumulate in PC-3 cellular mitochondria via organic anion transport peptide (OATP), increase ROS generation, and induce cancer cells apoptosis. In prostate cancer bearing xenografts, INH-dye conjugates showed significantly improved tumor-homing characteristics, resulting in potent antitumor activity via a reduction in MAOA activity. These results suggest that INH-dye conjugates have great potential to be used as versatile antitumor agents with prostate cancer targeting, NIR imaging, and potent antitumor efficacy.

PMID: 30468220 [PubMed - indexed for MEDLINE]

Can We Extrapolate Data from One Immune-Mediated Inflammatory Disease to Another One?

Curr Med Chem. 2019;26(2):248-258

Authors: Magro F, Coelho R, Peixoto A

Abstract
Immune-mediated inflammatory diseases share several pathogenic pathways and this pushes sometimes to extrapolate from one disease or indication to others. A biosimilar can be defined as a biotherapeutic product which is similar in terms of quality, safety, and efficacy to an already licensed reference biotherapeutic product. We review the substrate for extrapolation, the current approval process for biosimilars and the pioneering studies on biosimilars performed in rheumatoid arthritis patients. A biosimilar has the same amino acid sequence as its innovator product. However, post-translational modifications can occur and the current analytical techniques do not allow the final structure. To test the efficacy in one indication, a homogeneous population should be chosen and immunogenicity features are essential in switching and interchangeability. CT-P13 (Remsima™; Inflectra™) is a biosimilar of reference infliximab (Remicade®). It meets most of the requirements for extrapolation. Nevertheless, in inflammatory bowel diseases (IBD) we need more studies to confirm the postulates of extrapolation from rheumatoid arthritis and ankylosing spondylitis to IBD. Furthermore, an effective pharmacovigilance schedule is mandatory to look for immunogenicity and side effects.

PMID: 30381062 [PubMed - indexed for MEDLINE]

Targeting cytochrome P450-dependent cancer cell mitochondria: cancer associated CYPs and where to find them.

Cancer Metastasis Rev. 2018 09;37(2-3):409-423

Authors: Guo Z, Johnson V, Barrera J, Porras M, Hinojosa D, Hernández I, McGarrah P, Potter DA

Abstract
While cytochrome P450 (CYP)-mediated biosynthesis of arachidonic acid (AA) epoxides promotes tumor growth by driving angiogenesis, cancer cell intrinsic functions of CYPs are less understood. CYP-derived AA epoxides, called epoxyeicosatrienoic acids (EETs), also promote the growth of tumor epithelia. In cancer cells, CYP AA epoxygenase enzymes are associated with STAT3 and mTOR signaling, but also localize in mitochondria, where they promote the electron transport chain (ETC). Recently, the diabetes drug metformin was found to inhibit CYP AA epoxygenase activity, allowing the design of more potent biguanides to target tumor growth. Biguanide inhibition of EET synthesis suppresses STAT3 and mTOR pathways, as well as the ETC. Convergence of biguanide activity and eicosanoid biology in cancer has shown a new pathway to attack cancer metabolism and provides hope for improved treatments that target this vulnerability. Inhibition of EET-mediated cancer metabolism and angiogenesis therefore provides a dual approach for targeted cancer therapeutics.

PMID: 30066055 [PubMed - indexed for MEDLINE]

The antimalarial drug amodiaquine possesses anti-ZIKA virus activities.

J Med Virol. 2018 05;90(5):796-802

Authors: Han Y, Mesplède T, Xu H, Quan Y, Wainberg MA

Abstract
Zika virus (ZIKV) outbreak has emerged as a global health threat, particularly in tropical areas, over the past few years. No antiviral therapy or vaccine is available at present. For these reasons, repurposing clinically approved drugs against ZIKV infection may provide rapid and cost-effective global health benefits. Here, we explored this strategy and screened eight FDA-approved drugs for antiviral activity against ZIKV using a cell-based assay. Our results show that the antimalarial drug amodiaquine has anti-ZIKV activity with EC50 at low micromolar concentrations in cell culture. We further characterized amodiaquine antiviral activity against ZIKV and found that it targets early events of the viral replication cycle. Altogether, our results suggest that amodiaquine may be efficacious for the treatment of ZIKV infection.

PMID: 29315671 [PubMed - indexed for MEDLINE]

Drug repurposing of N-acetyl cysteine as antiviral against dengue virus infection.

Antiviral Res. 2019 Mar 27;:

Authors: Sreekanth GP, Panaampon J, Suttitheptumrong A, Chuncharunee A, Bootkunha J, Yenchitsomanus PT, Limjindaporn T

Abstract
Liver injury is one of the hallmark features of severe dengue virus (DENV) infection since DENV can replicate in the liver and induce hepatocytes to undergo apoptosis. N-acetyl cysteine (NAC), which is a clinically-used drug for treating acetaminophen toxicity, was found to benefit patients with DENV-induced liver injury; however, its mechanism of action remains unclear. Accordingly, our aim was to repurpose NAC in the preclinical studies to investigate its mechanism of action. Time of addition experiments in HepG2 cells elucidated effectiveness of NAC to reduce infectious virion at pre-, during- and post infection. In DENV-infected mice, NAC improved DENV-associated clinical manifestations, including leucopenia and thrombocytopenia, and reduced liver injury and hepatocyte apoptosis. Interestingly, we discovered that NAC significantly reduced DENV production in HepG2 cells and in liver of DENV-infected mice by induction of antiviral responses via interferon signaling. NAC treatment in DENV-infected mice helped to maintain antioxidant enzymes and redox balance in the liver. Therefore, NAC reduces DENV production and oxidative damage to ameliorate DENV-induced liver injury. Taken together, these findings suggest the novel therapeutic potential of NAC in DENV-induced liver injury and recommend evaluating its efficacy and safety in humans with DENV-induced liver injury.

PMID: 30928439 [PubMed - as supplied by publisher]