Evaluation of imidazole and its derivative against Newcastle disease virus infection in chicken: A drug repurposing approach.

Virus Res. 2018 Nov 30;:

Authors: Das M, Baro S, Kumar S

Abstract
Despite recent progress in vaccination options, Newcastle disease virus (NDV) stands a severe global epidemic and economic burden. It is difficult to control NDV with vaccination alone due to its evolving genetic variability; therefore, an effective therapeutic must target to resist its replication and further evolution. Drug repurposing is a practical and economical method to develop therapeutics against pathogenic organisms. Applying the knowledge of the broadly used antimicrobial activity of imidazole and its derivatives, we performed repurposing-based design of therapeutics to induce protection against NDV. We checked the ability of the compound at sub-lethal doses to reduce NDV replication in vitro, in ovo and in vivo. Chickens treated with the repurposed drug produced antiviral type I interferon and showed no shedding of the virus. Successful designing of novel NDV drug, in this study empirically demonstrates the principle that repurposing can be used for developing antiviral therapeutics.

PMID: 30508602 [PubMed - as supplied by publisher]

Use of statins or NSAIDs and survival of patients with high-grade glioma.

PLoS One. 2018;13(12):e0207858

Authors: Seliger C, Schaertl J, Gerken M, Luber C, Proescholdt M, Riemenschneider MJ, Leitzmann MF, Hau P, Klinkhammer-Schalke M

Abstract
BACKGROUND: High-grade glioma (HGG) is associated with a limited prognosis. Drug repurposing has become of increasing interest to improve standard therapy. Statins and NSAIDs inhibit glioma cell growth in vitro and in vivo, but data on statin and NSAID treatment in relation to survival of patients with HGG are sparse.
METHODS: We performed multivariable adjusted Cox-regression analyses among 1,093 patients with HGG from a regional cancer registry to obtain Hazard Ratios (HRs) with 95% Confidence Intervals (CIs) for overall survival (OS) and progression-free survival (PFS) according to treatment with statins or NSAIDs. Data on dose and duration of treatment was mostly lacking in our analysis, therefore we were not able to perform dose-response analyses.
RESULTS: Use of statins was unrelated to OS or PFS of glioma patients. Use of aspirin was associated with prolonged OS and PFS in patients with WHO grade III, but not WHO grade IV glioma. Use of other NSAIDs (diclofenac, ibuprofen) or non-NSAID analgesics (paracetamol) was mostly unrelated to survival of glioma patients. Use of selective COX-2 inhibitors and metamizol was related to inferior patient survival in parts of the analyses.
CONCLUSIONS: Use of statins or NSAIDS, including aspirin, was not associated with prolonged OS or PFS of patients with WHO grade IV glioma in our selected cohort. There was an indication for improved survival in patients with WHO grade III glioma using aspirin, but further studies are needed to confirm our first observation.

PMID: 30507932 [PubMed - in process]

AS602801, an Anticancer Stem Cell Candidate Drug, Reduces Survivin Expression and Sensitizes A2780 Ovarian Cancer Stem Cells to Carboplatin and Paclitaxel.

Anticancer Res. 2018 Dec;38(12):6699-6706

Authors: Yamamoto M, Suzuki S, Togashi K, Sanomachi T, Seino S, Kitanaka C, Okada M

Abstract
BACKGROUND: AS602801, a novel inhibitor of c-Jun N-terminal kinase (JNK), suppresses tumor initiation capacity and metastatic potential of cancer stem cells (CSCs). However, it remains unknown whether this inhibitor can chemosensitize CSCs.
MATERIALS AND METHODS: Using A2780 CSLC, a CSC line derived from ovarian cancer, this study examined the combinational effects of AS602801 and carboplatin or paclitaxel and explored the mechanism of those effects.
RESULTS: AS602801 chemosensitized A2780 CSLC cells to carboplatin and paclitaxel. With respect to the mechanism of chemosensitization, the expression of survivin, an anti-apoptotic protein, was reduced by AS602801. Pharmacological and genetic inhibition of survivin chemosensitized the cells to carboplatin and paclitaxel. Suppression of survivin by AS602801 was also observed in other types of CSCs and non-CSCs.
CONCLUSION: AS602801, which reduces survivin expression, can chemosensitize ovarian CSCs and is a candidate drug that targets the chemoresistance, tumor-initiating capacity and metastasis of CSCs.

PMID: 30504379 [PubMed - in process]

Understanding Membrane Protein Drug Targets in Computational Perspective.

Curr Drug Targets. 2018 Dec 04;:

Authors: Gong J, Tan X, Chen Y, Sun P, He F, Zhang L, Li Y, Ma Z, Wang H

Abstract
Membrane proteins play a crucial physiological role in vivo and are the major category of drug targets for pharmaceuticals. The research on membrane protein is a significant part in drug discovery due to a membrane protein can be regarded as a vital hub while most drug effect by drug-target interaction and the biological process can be supposed as a cycled network. In this review, typical membrane protein targets are described, including GPCRs, transporters, ion channels. In addition, network servers and databases referring to the drug and target information as well as drug discovery data are concluded. Furthermore, we chiefly introduce the development and practice of modern medicines, particularly demonstrating a series of state-of-the-art computational models for prediction of drug-target interaction containing network-based approach and machine learning based approach as well as current achievements. Finally, we discuss the prospective orientation of drug repurposing and drug discovery as well as propose some improved framework in quantitative bioactivity data, created or improved predicted approaches, alternative understanding approaches of drugs bioactivity and their biological processes.

PMID: 30516106 [PubMed - as supplied by publisher]

Identification of drug repurposing candidates based on a miRNA-mediated drug and pathway network for cardiac hypertrophy and acute myocardial infarction.

Hum Genomics. 2018 Dec 04;12(1):52

Authors: Sun J, Yang J, Chi J, Ding X, Lv N

Abstract
BACKGROUND: Cardiac hypertrophy and acute myocardial infarction (AMI) are two common heart diseases worldwide. However, research is needed into the exact pathogenesis and effective treatment strategies for these diseases. Recently, microRNAs (miRNAs) have been suggested to regulate the pathological pathways of heart disease, indicating a potential role in novel treatments.
RESULTS: In our study, we constructed a miRNA-gene-drug network and analyzed its topological features. We also identified some significantly dysregulated miRNA-gene-drug triplets (MGDTs) in cardiac hypertrophy and AMI using a computational method. Then, we characterized the activity score profile features for MGDTs in cardiac hypertrophy and AMI. The functional analyses suggested that the genes in the network held special functions. We extracted an insulin-like growth factor 1 receptor-related subnetwork in cardiac hypertrophy and a vascular endothelial growth factor A-related subnetwork in AMI. Finally, we considered insulin-like growth factor 1 receptor and vascular endothelial growth factor A as two candidate drug targets by utilizing the cardiac hypertrophy and AMI pathways.
CONCLUSION: These results provide novel insights into the mechanisms and treatment of cardiac hypertrophy and AMI.

PMID: 30514363 [PubMed - in process]

The drug repurposing landscape from 2012 to 2017: evolution, challenges, and possible solutions.

Drug Discov Today. 2018 Dec 01;:

Authors: Polamreddy P, Gattu N

Abstract
As the name suggests, drug repurposing is a strategy to identify new therapeutic uses for marketed drugs, discontinued and/or shelved drugs, and drug candidates currently in clinical development. Although not a recent concept, drug repurposing has gained momentum over the past few years and several drugs have been successfully repurposed. Here, we summarize the drug repurposing landscape from 2012 to 2017, with a major focus on repurposed drugs, collaborative opportunities, and funding opportunities specific to drug repurposing projects. Along with success stories, we also highlight the challenges and limitations associated with drug repurposing.

PMID: 30513339 [PubMed - as supplied by publisher]

Warburg effect in Gynecologic cancers.

J Obstet Gynaecol Res. 2018 Dec 03;:

Authors: Kobayashi Y, Banno K, Kunitomi H, Takahashi T, Takeda T, Nakamura K, Tsuji K, Tominaga E, Aoki D

Abstract
Mammalian cells produce energy by oxidative phosphorylation under aerobic conditions. However, in the 1920s, Otto Warburg reported the so-called "Warburg effect" in which cancer cells produce ATP that is biased toward glycolysis rather than mitochondrial oxidative phosphorylation not only in anaerobic environment but also in aerobic environment. Glucose is converted into lactate without going into mitochondria after being metabolized in glycolysis. Compared with oxidative phosphorylation, the glycolysis has a faster ATP production rate but it is very inefficient, resulting in cancer cells consuming a large amount of glucose. Increased glucose metabolism has become a biomarker for cancer cells and has led to the development of positron emission tomography with fluorodeoxyglucose. Till date, the Warburg effect has been an inefficient system for cancer cells with regard to efficient energy production, but since the consumption of oxygen can be suppressed as the tumor grows in mass, it is thought that the Warburg effect is advantageous in this situation wherein the tumor can increase despite the lack of vessels. In addition, an increased lactate by the glycolysis causes acidosis in the microenvironment of tissues, which is thought to damage the surrounding normal tissues and favor the invasion and metastasis of cancer. Thus, Warburg effect is one of the key mechanisms for cancer development and will be the next promising target. In this review, we introduce key players that can be targeted in the Warburg effect and outline the prospects of treatment, targeting the Warburg effect in gynecological cancer.

PMID: 30511455 [PubMed - as supplied by publisher]

Repurposing approach identifies new treatment options for invasive fungal disease.

Bioorg Chem. 2018 Nov 19;84:87-97

Authors: Capoci IRG, Faria DR, Sakita KM, Rodrigues-Vendramini FAV, Bonfim-Mendonça PS, Becker TCA, Kioshima ÉS, Svidzinski TIE, Maigret B

Abstract
Drug repositioning is the process of discovery, validation and marketing of previously approved drugs for new indications. Our aim was drug repositioning, using ligand-based and structure-based computational methods, of compounds that are similar to two hit compounds previously selected by our group that show promising antifungal activity. Through the ligand-based method, 100 compounds from each of three databases (MDDR, DrugBank and TargetMol) were selected by the Tanimoto coefficient, as similar to LMM5 or LMM11. These compounds were analyzed by the scaffold trees, and up to 10 compounds from each database were selected. The structure-based method (molecular docking) using thioredoxin reductase as the target drug was performed as a complementary approach, resulting in six compounds that were tested in an in vitro assay. All compounds, particularly raltegravir, showed antifungal activity against the genus Paracoccidioides. Raltegravir, an antiviral drug, showed promising antifungal activity against the experimental murine paracoccidioidomycosis, with significant reduction of the fungal burden and decreased alterations in the lung structure of mice treated with 1 mg/kg of raltegravir. In conclusion, the combination of two in silico methods for drug repositioning was able to select an antiviral drug with promising antifungal activity for treatment of paracoccidioidomycosis.

PMID: 30496872 [PubMed - as supplied by publisher]

Paradigm Shift in Drug Re-purposing From Phenalenone to Phenaleno-Furanone to Combat Multi-Drug Resistant Salmonella enterica Serovar Typhi.

Front Cell Infect Microbiol. 2018;8:402

Authors: Mujawar S, Gatherer D, Lahiri C

Abstract
Over recent years, typhoid fever has gained increasing attention with several cases reporting treatment failure due to multidrug resistant (MDR) strains of Salmonella enterica serovar Typhi. While new drug development strategies are being devised to combat the threat posed by these MDR pathogens, drug repurposing or repositioning has become a good alternative. The latter is considered mainly due to its capacity for saving sufficient time and effort for pre-clinical and optimization studies. Owing to the possibility of an unsuccessful repositioning, due to the mismatch in the optimization of the drug ligand for the changed biochemical properties of "old" and "new" targets, we have chosen a "targeted" approach of adopting a combined chemical moiety-based drug repurposing. Using small molecules selected from a combination of earlier approved drugs having phenalenone and furanone moieties, we have computationally delineated a step-wise approach to drug design against MDR Salmonella. We utilized our network analysis-based pre-identified, essential chaperone protein, SicA, which regulates the folding and quality of several secretory proteins including the Hsp70 chaperone, SigE. To this end, another crucial chaperone protein, Hsp70 DnaK, was also considered due to its importance for pathogen survival under the stress conditions typically encountered during antibiotic therapies. These were docked with the 19 marketed anti-typhoid drugs along with two phenalenone-furanone derivatives, 15 non-related drugs which showed 70% similarity to phenalenone and furanone derivatives and other analogous small molecules. Furthermore, molecular dynamics simulation studies were performed to check the stability of the protein-drug complexes. Our results showed the best binding interaction and stability, under the parameters of a virtual human body environment, with XR770, a phenaleno-furanone moiety based derivative. We therefore propose XR770, for repurposing for therapeutic intervention against emerging and significant drug resistance conferred by pathogenic Salmonella strains.

PMID: 30488026 [PubMed - in process]

Drug repurposing: Heart failure drug effective in medulloblastoma.

Nat Rev Drug Discov. 2018 Nov 28;17(12):864

Authors: Crunkhorn S

PMID: 30482959 [PubMed - in process]

Columbia Open Health Data, clinical concept prevalence and co-occurrence from electronic health records.

Sci Data. 2018 Nov 27;5:180273

Authors: Ta CN, Dumontier M, Hripcsak G, Tatonetti NP, Weng C

Abstract
Columbia Open Health Data (COHD) is a publicly accessible database of electronic health record (EHR) prevalence and co-occurrence frequencies between conditions, drugs, procedures, and demographics. COHD was derived from Columbia University Irving Medical Center's Observational Health Data Sciences and Informatics (OHDSI) database. The lifetime dataset, derived from all records, contains 36,578 single concepts (11,952 conditions, 12,334 drugs, and 10,816 procedures) and 32,788,901 concept pairs from 5,364,781 patients. The 5-year dataset, derived from records from 2013-2017, contains 29,964 single concepts (10,159 conditions, 10,264 drugs, and 8,270 procedures) and 15,927,195 concept pairs from 1,790,431 patients. Exclusion of rare concepts (count ≤ 10) and Poisson randomization enable data sharing by eliminating risks to patient privacy. EHR prevalences are informative of healthcare consumption rates. Analysis of co-occurrence frequencies via relative frequency analysis and observed-expected frequency ratio are informative of associations between clinical concepts, useful for biomedical research tasks such as drug repurposing and pharmacovigilance. COHD is publicly accessible through a web application-programming interface (API) and downloadable from the Figshare repository. The code is available on GitHub.

PMID: 30480666 [PubMed - in process]

Current state and outlook for drug repositioning anticipated in the field of ovarian cancer.

J Gynecol Oncol. 2018 Oct 08;:

Authors: Kobayashi Y, Banno K, Kunitomi H, Tominaga E, Aoki D

Abstract
Ovarian cancer is the seventh most common cancer and the eighth most common cause of cancer mortality in women. Although standard chemotherapy is the established treatment for ovarian cancer, the prognosis remains poor, and it is highly anticipated that new drugs will be developed. New drugs, such as humanized anti-vascular endothelial growth factor monoclonal antibodies and poly ADP-ribose polymerase inhibitors, are expected to improve clinical outcomes of ovarian cancer. However, long-term, costly research is required to develop such new drugs, and soaring national healthcare costs are becoming a concern worldwide. In this social context, drug repositioning, wherein existing drugs are used to develop drugs with new indications for other diseases, has recently gained attention. Because trials have already confirmed the safety in humans and the pharmacokinetics of such drugs, the development period is shorter than the conventional development of a new drug, thereby reducing costs. This review discusses the available basic experimental and clinical data on drugs used for other types of cancer for which drug repositioning is anticipated to repurpose the drug for the treatment of ovarian cancer. These include statins, which are used to treat dyslipidemia; bisphosphonate, which is used to treat osteoporosis; metformin, which is used to treat diabetes; non-steroidal anti-inflammatory drugs; ivermectin, an antiparasitic agent; and itraconazole, an anti-fungal agent. These drugs will play an important role in future drug repositioning strategies for ovarian cancer. Furthermore, drug repositioning is anticipated to extend not only to ovarian cancer treatment but also to ovarian cancer prevention.

PMID: 30479094 [PubMed - as supplied by publisher]

Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review.

JAMA Neurol. 2018 Nov 26;:

Authors: Chohan MO, Marchiò S, Morrison LA, Sidman RL, Cavenee WK, Dejana E, Yonas H, Pasqualini R, Arap W

Abstract
Importance: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality.
Observations: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions.
Conclusions and Relevance: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

PMID: 30476961 [PubMed - as supplied by publisher]

[Langanhaltende Besserung von somatischen und psychovegetativen Störungen unter Procain-Infusionen: Eine multizentrische Anwendungsbeobachtung].

Complement Med Res. 2018 Nov 24;:

Authors: Hahn-Godeffroy JD, Mangold S, Bernert M, Bartelt A, Herdegen T

Abstract
Hintergrund: Procain besitzt wie das strukturverwandte Cocain zentralnervöse Wirkungen unabhängig von seinem lokalanästhetischen Effekt. Procain-Infusionen werden Patienten mit psychovegetativen Störungen seit Jahrzehnten verabreicht, zumeist im Rahmen einer Neuraltherapie. Untersuchungen zur Wirksamkeit einer alleinigen Gabe von Procain im Praxisalltag stehen aus. Patienten und Methoden: Im Rahmen einer Anwendungsbeobachtung (AWB) wurde bei 56 Patienten aus 3 Arztpraxen die Wirkung von intravenösen Procain-Infusionen (1-3 Ampullen à 5 ml einer 2%igen Procain-Lösung in 250 ml Natriumchlorid pro Arztbesuch) auf das somatische und psychovegetative Befinden dokumentiert. Hierzu wurde ein validierter, 21 Fragen umfassender Befindlichkeitsskalierungsfragebogen verwendet, den die Patienten vor Beginn und nach 1, 2, 4 und 6 Monaten ausfüllten. Neben der laufenden Medikation waren keine weiteren therapeutischen Maßnahmen erlaubt. Ergebnisse: Nach 4 oder 6 Monaten zeigten 42 Patienten (75%) eine Verbesserung bei den 9 positiven Items (d.h. erfragte Eigenschaften) wie «Freude», «Genussfähigkeit» oder «Schlaf»; 35 Patienten (62,5%) verbesserten sich bei den 12 negativen Items wie «Stressbelastung», «Energielosigkeit» oder «Ängstlichkeit». Diese Veränderungen waren nach 2, 4 und 6 Monaten signifikant gegenüber dem Ausgangswert. Schlussfolgerungen: Procain ruft im zentralen Nervensystem nachweislich Veränderungen in der Aktivität spezifischer Kerngebiete wie des limbischen und kortikalen Systems hervor. Die Ergebnisse dieser AWB deuten auf eine langanhaltende Verbesserung von somatischen und psychovegetativen Störungen unter der Infusion von Procain.

PMID: 30476918 [PubMed - as supplied by publisher]

Sertraline, Paroxetine, and Chlorpromazine Are Rapidly Acting Anthelmintic Drugs Capable of Clinical Repurposing.

Sci Rep. 2018 01 17;8(1):975

Authors: Weeks JC, Roberts WM, Leasure C, Suzuki BM, Robinson KJ, Currey H, Wangchuk P, Eichenberger RM, Saxton AD, Bird TD, Kraemer BC, Loukas A, Hawdon JM, Caffrey CR, Liachko NF

Abstract
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults. These drugs act rapidly to inhibit C. elegans feeding within minutes of exposure. Sertraline, paroxetine, and chlorpromazine also decrease motility of adult Trichuris muris whipworms, prevent hatching and development of Ancylostoma caninum hookworms and kill Schistosoma mansoni flatworms, three widely divergent parasitic helminth species. C. elegans mutants with resistance to known anthelmintic drugs such as ivermectin are equally or more susceptible to these three drugs, suggesting that they may act on novel targets to kill worms. Sertraline, paroxetine, and chlorpromazine have long histories of use clinically as antidepressant or antipsychotic medicines. They may represent new classes of anthelmintic drug that could be used in combination with existing front-line drugs to boost effectiveness of anti-parasite treatment as well as offset the development of parasite drug resistance.

PMID: 29343694 [PubMed - indexed for MEDLINE]

Cromolyn Reduces Levels of the Alzheimer's Disease-Associated Amyloid β-Protein by Promoting Microglial Phagocytosis.

Sci Rep. 2018 01 18;8(1):1144

Authors: Zhang C, Griciuc A, Hudry E, Wan Y, Quinti L, Ward J, Forte AM, Shen X, Ran C, Elmaleh DR, Tanzi RE

Abstract
Amyloid-beta protein (Aβ) deposition is a pathological hallmark of Alzheimer's disease (AD). Aβ deposition triggers both pro-neuroinflammatory microglial activation and neurofibrillary tangle formation. Cromolyn sodium is an asthma therapeutic agent previously shown to reduce Aβ levels in transgenic AD mouse brains after one-week of treatment. Here, we further explored these effects as well as the mechanism of action of cromolyn, alone, and in combination with ibuprofen in APPSwedish-expressing Tg2576 mice. Mice were treated for 3 months starting at 5 months of age, when the earliest stages of β-amyloid deposition begin. Cromolyn, alone, or in combination with ibuprofen, almost completely abolished longer insoluble Aβ species, i.e. Aβ40 and Aβ42, but increased insoluble Aβ38 levels. In addition to its anti-aggregation effects on Aβ, cromolyn, alone, or plus ibuprofen, but not ibuprofen alone, increased microglial recruitment to, and phagocytosis of β-amyloid deposits in AD mice. Cromolyn also promoted Aβ42 uptake in microglial cell-based assays. Collectively, our data reveal robust effects of cromolyn, alone, or in combination with ibuprofen, in reducing aggregation-prone Aβ levels and inducing a neuroprotective microglial activation state favoring Aβ phagocytosis versus a pro-neuroinflammatory state. These findings support the use of cromolyn, alone, or with ibuprofen, as a potential AD therapeutic.

PMID: 29348604 [PubMed - indexed for MEDLINE]

To Zika and destroy: an antimalarial drug protects fetuses from Zika infection.

Future Microbiol. 2018 02;13:137-139

Authors: Cao B, Sheth MN, Mysorekar IU

PMID: 29302996 [PubMed - indexed for MEDLINE]

Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase.

BMC Res Notes. 2018 Nov 21;11(1):825

Authors: Castilho VVS, Gonçalves KCS, Rebello KM, Baptista LPR, Sangenito LS, Santos HLC, Branquinha MH, Santos ALS, Menna-Barreto RFS, Guimarães AC, d'Avila-Levy CM

Abstract
OBJECTIVE: The low investment in research, diagnosis and treatment are factors that contribute to the continuity of Chagas' disease as a neglected tropical diseases (NTDs). In this context, the repositioning of drugs represents a useful strategy, in the search for new chemotherapeutic approaches for NTDs. HIV aspartic peptidase inhibitors (HIV IPs) are good candidates for drug repurposing. Here, we modeled the three dimensional structure of an aspartyl peptidase of Trypanosoma cruzi, the causative agent of Chagas' disease, aligned it to the HIV aspartyl peptidase and performed docking binding assays with the HIV PIs.
RESULTS: The 3D structure confirmed the presence of acid aspartic residues, which are critical to enzyme activity. The docking experiment revealed that HIV IPs bind to the active site of the enzyme, being ritonavir and lopinavir the ones with greater affinity. Benznidazole presented the worst binding affinity, this drug is currently used in Chagas' disease treatment and was included as negative control. These results together with previous data on the trypanocidal effect of the HIV PIs support the hypothesis that a T. cruzi aspartyl peptidase can be the intracellular target of these inhibitors. However, the direct demonstration of the inhibition of T. cruzi aspartyl peptidase activity by HIV PIs is still a goal to be persuaded.

PMID: 30463602 [PubMed - in process]

Drug repositioning using drug-disease vectors based on an integrated network.

BMC Bioinformatics. 2018 Nov 21;19(1):446

Authors: Lee T, Yoon Y

Abstract
BACKGROUND: Diverse interactions occur between biomolecules, such as activation, inhibition, expression, or repression. However, previous network-based studies of drug repositioning have employed interaction on the binary protein-protein interaction (PPI) network without considering the characteristics of the interactions. Recently, some studies of drug repositioning using gene expression data found that associations between drug and disease genes are useful information for identifying novel drugs to treat diseases. However, the gene expression profiles for drugs and diseases are not always available. Although gene expression profiles of drugs and diseases are available, existing methods cannot use the drugs or diseases, when differentially expressed genes in the profiles are not included in their network.
RESULTS: We developed a novel method for identifying candidate indications of existing drugs considering types of interactions between biomolecules based on known drug-disease associations. To obtain associations between drug and disease genes, we constructed a directed network using protein interaction and gene regulation data obtained from various public databases providing diverse biological pathways. The network includes three types of edges depending on relationships between biomolecules. To quantify the association between a target gene and a disease gene, we explored the shortest paths from the target gene to the disease gene and calculated the types and weights of the shortest paths. For each drug-disease pair, we built a vector consisting of values for each disease gene influenced by the drug. Using the vectors and known drug-disease associations, we constructed classifiers to identify novel drugs for each disease.
CONCLUSION: We propose a method for exploring candidate drugs of diseases using associations between drugs and disease genes derived from a directed gene network instead of gene regulation data obtained from gene expression profiles. Compared to existing methods that require information on gene relationships and gene expression data, our method can be applied to a greater number of drugs and diseases. Furthermore, to validate our predictions, we compared the predictions with drug-disease pairs in clinical trials using the hypergeometric test, which showed significant results. Our method also showed better performance compared to existing methods for the area under the receiver operating characteristic curve (AUC).

PMID: 30463505 [PubMed - in process]

Beyond members of the Flaviviridae family, sofosbuvir also inhibits chikungunya virus replication.

Antimicrob Agents Chemother. 2018 Nov 19;:

Authors: Ferreira AC, Reis PA, de Freitas CS, Sacramento CQ, Villas Bôas Hoelz L, Bastos MM, Mattos M, Rocha N, Gomes de Azevedo Quintanilha I, da Silva Gouveia Pedrosa C, Rocha Quintino Souza L, Correia Loiola E, Trindade P, Rangel Vieira Y, Barbosa-Lima G, de Castro Faria Neto HC, Boechat N, Rehen SK, Brüning K, Bozza FA, Bozza PT, Souza TML

Abstract
Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae, not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir compared to the hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg/day, and prevented mortality in a neonate mouse model at 40 and 80 mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.

PMID: 30455237 [PubMed - as supplied by publisher]