Expanding the activity spectrum of antiviral agents.

Drug Discov Today. 2019 05;24(5):1224-1228

Authors: Ianevski A, Andersen PI, Merits A, Bjørås M, Kainov D

Abstract
Broad-spectrum antivirals (BSAs) are agents that inhibit replication of several human viruses. Here, we review 108 approved, investigational, and experimental BSAs, for which safety profiles in humans are available. The most effective and tolerable BSAs could reinforce the arsenal of available antiviral therapeutics pending the results of further pre-clinical and clinical studies.

PMID: 30980905 [PubMed - indexed for MEDLINE]

In Silico and In Vitro Experimental Studies of New Dibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)-oximes Designed as Potential Antimicrobial Agents.

Molecules. 2020 Jan 13;25(2):

Authors: Vlad IM, Nuta DC, Chirita C, Caproiu MT, Draghici C, Dumitrascu F, Bleotu C, Avram S, Udrea AM, Missir AV, Marutescu LG, Limban C

Abstract
In a drug-repurposing-driven approach for speeding up the development of novel antimicrobial agents, this paper presents for the first time in the scientific literature the synthesis, physico-chemical characterization, in silico analysis, antimicrobial activity against bacterial and fungal strains in planktonic and biofilm growth state, as well as the in vitro cytotoxicity of some new 6,11-dihydrodibenz[b,e]oxepin-11(6H)one O-(arylcarbamoyl)oximes. The structures of intermediary and final substances (compounds 7a-j) were confirmed by 1H-NMR, 13C-NMR and IR spectra, as well as by elemental analysis. The in silico bioinformatic and cheminformatic studies evidenced an optimal pharmacokinetic profile for the synthesized compounds 7a-j, characterized by an average lipophilic character predicting good cell membrane permeability and intestinal absorption; low maximum tolerated dose for humans; potassium channels encoded by the hERG I and II genes as potential targets and no carcinogenic effects. The obtained compounds exhibited a higher antimicrobial activity against the planktonic Gram-positive Staphylococcus aureus and Bacillus subtilis strains and the Candida albicans fungal strain. The obtained compounds also inhibited the ability of S. aureus, B. subtilis, Escherichia coli and C. albicans strains to colonize the inert substratum, accounting for their possible use as antibiofilm agents. All the active compounds exhibited low or acceptable cytotoxicity levels on the HCT8 cells, ensuring the potential use of these compounds for the development of new antimicrobial drugs with minimal side effects on the human cells and tissues.

PMID: 31941125 [PubMed - in process]

Sitravatinib Sensitizes ABCB1- and ABCG2-Overexpressing Multidrug-Resistant Cancer Cells to Chemotherapeutic Drugs.

Cancers (Basel). 2020 Jan 13;12(1):

Authors: Wu CP, Hsiao SH, Huang YH, Hung LC, Yu YJ, Chang YT, Hung TH, Wu YS

Abstract
The development of multidrug resistance (MDR) in cancer patients driven by the overexpression of ATP-binding cassette (ABC) transporter ABCB1 or ABCG2 in cancer cells presents one of the most daunting therapeutic complications for clinical scientists to resolve. Despite many novel therapeutic strategies that have been tested over the years, there is still no approved treatment for multidrug-resistant cancers to date. We have recently adopted a drug repurposing approach to identify therapeutic agents that are clinically active and at the same time, capable of reversing multidrug resistance mediated by ABCB1 and ABCG2. In the present study, we investigated the effect of sitravatinib, a novel multitargeted receptor tyrosine kinase inhibitor, on human ABCB1 and ABCG2 in multidrug-resistant cancer cell lines. We discovered that at submicromolar concentrations, sitravatinib re-sensitizes ABCB1- and ABCG2-overexpressing multidrug-resistant cancer cells to chemotherapeutic drugs. We found that sitravatinib blocks the drug efflux function of ABCB1 and ABCG2 in a concentration-dependent manner but does not significantly alter the protein expression of ABCB1 or ABCG2 in multidrug-resistant cancer cells. In conclusion, we reveal a potential drug repositioning treatment option for multidrug-resistant cancers by targeting ABCB1 and ABCG2 with sitravatinib and should be further investigated in future clinical trials.

PMID: 31941029 [PubMed]

Pharmacological Chaperones: A Therapeutic Approach for Diseases Caused by Destabilizing Missense Mutations.

Int J Mol Sci. 2020 Jan 13;21(2):

Authors: Liguori L, Monticelli M, Allocca M, Hay Mele B, Lukas J, Cubellis MV, Andreotti G

Abstract
The term "pharmacological chaperone" was introduced 20 years ago. Since then the approach with this type of drug has been proposed for several diseases, lysosomal storage disorders representing the most popular targets. The hallmark of a pharmacological chaperone is its ability to bind a protein specifically and stabilize it. This property can be beneficial for curing diseases that are associated with protein mutants that are intrinsically active but unstable. The total activity of the affected proteins in the cell is lower than normal because they are cleared by the quality control system. Although most pharmacological chaperones are reversible competitive inhibitors or antagonists of their target proteins, the inhibitory activity is neither required nor desirable. This issue is well documented by specific examples among which those concerning Fabry disease. Direct specific binding is not the only mechanism by which small molecules can rescue mutant proteins in the cell. These drugs and the properly defined pharmacological chaperones can work together with different and possibly synergistic modes of action to revert a disease phenotype caused by an unstable protein.

PMID: 31940970 [PubMed - in process]

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Nat Commun. 2020 Jan 14;11(1):255

Authors: Li YR, Glessner JT, Coe BP, Li J, Mohebnasab M, Chang X, Connolly J, Kao C, Wei Z, Bradfield J, Kim C, Hou C, Khan M, Mentch F, Qiu H, Bakay M, Cardinale C, Lemma M, Abrams D, Bridglall-Jhingoor A, Behr M, Harrison S, Otieno G, Thomas A, Wang F, Chiavacci R, Wu L, Hadley D, Goldmuntz E, Elia J, Maris J, Grundmeier R, Devoto M, Keating B, March M, Pellagrino R, Grant SFA, Sleiman PMA, Li M, Eichler EE, Hakonarson H

Abstract
Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

PMID: 31937769 [PubMed - in process]

[Congenital myasthenic syndromes: repurposing does not simplify access de facto - Clinical use of innovative, repurposed or off-label therapies: a real life experience (4)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:28-31

Authors: Eymard B

PMID: 30943158 [PubMed - indexed for MEDLINE]

[Accompanying patients in the arrival of new treatments. The AFM-Téléthon regional services experience - Clinical use of innovative, repurposed or off-label therapies: a real life experience (3)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:26-27

Authors: Merret G

PMID: 30943157 [PubMed - indexed for MEDLINE]

[Nusinersen in SMA children: evolution or revolution? - Clinical use of innovative, repurposed or off-label therapies: a real life experience (2)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:22-25

Authors: Richelme C

PMID: 30943156 [PubMed - indexed for MEDLINE]

[Late-onset Pompe disease: the lessons drawn from the use of Myosime® - Clinical use of innovative, repurposed or off-label therapies: a real life experience (1)].

Med Sci (Paris). 2019 Mar;35 Hors série n° 1:18-21

Authors: Laforêt P

PMID: 30943155 [PubMed - indexed for MEDLINE]

Development of Inhalable Quinacrine Loaded Bovine Serum Albumin Modified Cationic Nanoparticles: Repurposing Quinacrine for Lung Cancer Therapeutics.

Int J Pharm. 2020 Jan 11;:118995

Authors: Vaidya B, Kulkarni NS, Shukla SK, Parvathaneni V, Chauhan G, Damon JK, Sarode A, V Garcia J, Kunda N, Mitragotri S, Gupta V

Abstract
Drug repurposing is on the rise as an atypical strategy for discovery of new molecules, involving use of pre-existing molecules for a different therapeutic application than the approved indication. Using this strategy, the current study aims to leverage effects of quinacrine (QA), a well-known anti-malarial drug, for treatment of non-small cell lung cancer (NSCLC). For respiratory diseases, designing a QA loaded inhalable delivery system has multiple advantages over invasive delivery. QA-loaded nanoparticles (NPs) were thus prepared using polyethyleneimine (PEI) as a cationic stabilizer. While the use of PEI provided cationic charge on the particles, it also mediated a burst release of QA and demonstrated potential particle toxicity. These concerns were circumvented by coating nanoparticles with bovine serum albumin (BSA), which retained the cationic charge, reduced NP toxicity and modulated QA release. Prepared nanoparticles were characterized for physicochemical properties along with their aerosolization potential. Therapeutic efficacy of the formulations was tested in different NSCLC cells. Mechanism of higher anti-proliferation was evaluated by studying cell cycle profile, apoptosis and molecular markers involved in the progression of lung cancer. BSA coated QA nanoparticles demonstrated good aerosolization potential with a mass median aerodynamic diameter of significantly less than 5µm. Nanoparticles also demonstrated improved therapeutic efficacy against NSCLC cells in terms of low IC50 values, cell cycle arrest at G2/M phase and autophagy inhibition leading to increased apoptosis. BSA coated QA NPs also demonstrated enhanced therapeutic efficacy in a 3D cell culture model. The present study thus lays solid groundwork for pre-clinical and eventual clinical studies as a standalone therapy and in combination with existing chemotherapeutics.

PMID: 31935471 [PubMed - as supplied by publisher]

Repurposing an HIV Drug for Zika Virus Therapy.

Mol Ther. 2019 12 04;27(12):2064-2066

Authors: Xie X, Shi PY

PMID: 31624014 [PubMed - indexed for MEDLINE]

Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa.

ACS Infect Dis. 2019 01 11;5(1):141-151

Authors: Hubble VB, Hubbard BA, Minrovic BM, Melander RJ, Melander C

Abstract
A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.

PMID: 30444345 [PubMed - indexed for MEDLINE]

Antibacterial activity of griseofulvin analogs as example of drug repurposing.

Int J Antimicrob Agents. 2020 Jan 10;:105884

Authors: Geronikaki A, Kartsev V, Petrou A, Akrivou MG, Vizirianakis IS, Chatzopoulou FM, Lichitsky B, Sirakanyan S, Kostic M, Smiljkovic M, Soković M, Druzhilovskiy D, Poroikov V

Abstract
Griseofulvin is a well-known antifungal drug launched in 1962 by Merck & Co. for treatment of dermatophyte infections. However, according to the predictions using Way2Drug computational drug repurposing platform, it may have antibacterial activity. Since no faultless confirmation of this prediction was found in the published literature, we estimated in silico antibacterial activity for 42 griseofulvin derivatives synthesized earlier. Antibacterial activity was predicted for 33 from 42 molecules, which lead to the conclusion that this activity might be considered as typical for the appropriate chemical series. Therefore, the experimental testing of antibacterial activity was performed on a panel of gram-positive and gram-negative microorganisms. The antibacterial activity was evaluated using the microdilution method detecting the minimal inhibitory (MIC) and minimal bactericidal (MBC) concentrations. The tested compounds exhibited the potent antibacterial activity against all the studied bacteria, with MIC and MBC ranging from 0.0037-0.04 mg/ml and 0.01-0.16 mg/ml, respectively. Their activity exceeded 2.5 to 12 times those of the ampicillin and 2 to 8 times those of the streptomycin, which were used as the reference drugs. Similarity analysis for all 42 compounds with the about 470 thousand drug-like compounds indexed by Clarivate Analytics Integrity database confirmed the significant novelty of the antibacterial activity for the compounds from this chemical class. Therefore, our study demonstrated that by computer-aided prediction of biological activity spectra for a particular chemical series it is possible to identify typical biological activities, which may be used for discovery of new applications for those molecules, e.g., drug repurposing.

PMID: 31931149 [PubMed - as supplied by publisher]

Ropinirole, a New ALS Drug Candidate Developed Using iPSCs.

Trends Pharmacol Sci. 2020 Jan 08;:

Authors: Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S

Abstract
Induced pluripotent stem cells (iPSCs) are increasingly used in the study of disease mechanisms and the development of effective disease-modifying therapies for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Recently, three candidate anti-ALS drugs - ropinirole (ROPI), retigabine, and bosutinib - have been identified in iPSC-based drug screens and are now being evaluated in clinical trials for safety and effectiveness. We review the preclinical data, clinical research design, and rationale for ROPI as an anti-ALS drug candidate compared with those of the other two drugs. We also discuss the use of iPSCs for understanding and monitoring treatment response as well as for new insights into the development of new drugs and therapeutic interventions for major neurodegenerative diseases.

PMID: 31926602 [PubMed - as supplied by publisher]

Metabolomics-Driven Exploration of the Chemical Drug Space to Predict Combination Antimicrobial Therapies.

Mol Cell. 2019 06 20;74(6):1291-1303.e6

Authors: Campos AI, Zampieri M

Abstract
Alternative to the conventional search for single-target, single-compound treatments, combination therapies can open entirely new opportunities to fight antibiotic resistance. However, combinatorial complexity prohibits experimental testing of drug combinations on a large scale, and methods to rationally design combination therapies are lagging behind. Here, we developed a combined experimental-computational approach to predict drug-drug interactions using high-throughput metabolomics. The approach was tested on 1,279 pharmacologically diverse drugs applied to the gram-negative bacterium Escherichia coli. Combining our metabolic profiling of drug response with previously generated metabolic and chemogenomic profiles of 3,807 single-gene deletion strains revealed an unexpectedly large space of inhibited gene functions and enabled rational design of drug combinations. This approach is applicable to other therapeutic areas and can unveil unprecedented insights into drug tolerance, side effects, and repurposing. The compendium of drug-associated metabolome profiles is available at https://zampierigroup.shinyapps.io/EcoPrestMet, providing a valuable resource for the microbiological and pharmacological communities.

PMID: 31047795 [PubMed - indexed for MEDLINE]

Construction of asthma related competing endogenous RNA network revealed novel long non-coding RNAs and potential new drugs.

Respir Res. 2020 Jan 10;21(1):14

Authors: Liao Y, Li P, Wang Y, Chen H, Ning S, Su D

Abstract
BACKGROUND: Asthma is a heterogeneous disease characterized by chronic airway inflammation. Long non-coding RNA can act as competing endogenous RNA to mRNA, and play significant role in many diseases. However, there is little known about the profiles of long non-coding RNA and the long non-coding RNA related competing endogenous RNA network in asthma. In current study, we aimed to explore the long non-coding RNA-microRNA-mRNA competing endogenous RNA network in asthma and their potential implications for therapy and prognosis.
METHODS: Asthma-related gene expression profiles were downloaded from the Gene Expression Omnibus database, re-annotated with these genes and identified for asthma-associated differentially expressed mRNAs and long non-coding RNAs. The long non-coding RNA-miRNA interaction data and mRNA-miRNA interaction data were downloaded using the starBase database to construct a long non-coding RNA-miRNA-mRNA global competing endogenous RNA network and extract asthma-related differentially expressed competing endogenous RNA network. Finally, functional enrichment analysis and drug repositioning of asthma-associated differentially expressed competing endogenous RNA networks were performed to further identify key long non-coding RNAs and potential therapeutics associated with asthma.
RESULTS: This study constructed an asthma-associated competing endogenous RNA network, determined 5 key long non-coding RNAs (MALAT1, MIR17HG, CASC2, MAGI2-AS3, DAPK1-IT1) and identified 8 potential new drugs (Tamoxifen, Ruxolitinib, Tretinoin, Quercetin, Dasatinib, Levocarnitine, Niflumic Acid, Glyburide).
CONCLUSIONS: The results suggested that long non-coding RNA played an important role in asthma, and these novel long non-coding RNAs could be potential therapeutic target and prognostic biomarkers. At the same time, potential new drugs for asthma treatment have been discovered through drug repositioning techniques, providing a new direction for the treatment of asthma.

PMID: 31924195 [PubMed - in process]

Editorial: Innovative Therapeutic and Vaccine Approaches Against Respiratory Pathogens.

Front Immunol. 2019;10:2960

Authors: Calzas C, Descamps D, Chignard M, Chevalier C

PMID: 31921201 [PubMed - in process]

Drug repurposing towards targeting cancer stem cells in pediatric brain tumors.

Cancer Metastasis Rev. 2020 Jan 09;:

Authors: Bahmad HF, Elajami MK, El Zarif T, Bou-Gharios J, Abou-Antoun T, Abou-Kheir W

Abstract
In the pediatric population, brain tumors represent the most commonly diagnosed solid neoplasms and the leading cause of cancer-related deaths globally. They include low-grade gliomas (LGGs), medulloblastomas (MBs), and other embryonal, ependymal, and neuroectodermal tumors. The mainstay of treatment for most brain tumors includes surgical intervention, radiation therapy, and chemotherapy. However, resistance to conventional therapy is widespread, which contributes to the high mortality rates reported and lack of improvement in patient survival despite advancement in therapeutic research. This has been attributed to the presence of a subpopulation of cells, known as cancer stem cells (CSCs), which reside within the tumor bulk and maintain self-renewal and recurrence potential of the tumor. An emerging promising approach that enables identifying novel therapeutic strategies to target CSCs and overcome therapy resistance is drug repurposing or repositioning. This is based on using previously approved drugs with known pharmacokinetic and pharmacodynamic characteristics for indications other than their traditional ones, like cancer. In this review, we provide a synopsis of the drug repurposing methodologies that have been used in pediatric brain tumors, and we argue how this selective compilation of approaches, with a focus on CSC targeting, could elevate drug repurposing to the next level.

PMID: 31919619 [PubMed - as supplied by publisher]

N-acetylcysteine reduces amphotericin B deoxycholate nephrotoxicity and improves the outcome of murine cryptococcosis.

Med Mycol. 2020 Jan 09;:

Authors: Magalhães TFF, Costa MC, Holanda RA, Ferreira GF, Carvalho VSD, Freitas GJC, Ribeiro NQ, Emídio ECP, Carmo PHF, de Brito CB, de Souza DG, Rocha CEV, Paixão TA, de Resende-Stoianoff MA, Santos DA

Abstract
Cryptococcosis is a life-threatening fungal infection, and its current treatment is toxic and subject to resistance. Drug repurposing represents an interesting approach to find drugs to reduce the toxicity of antifungals. In this study, we evaluated the combination of N-acetylcysteine (NAC) with amphotericin B (AMB) for the treatment of cryptococcosis. We examined the effects of NAC on fungal morphophysiology and on the macrophage fungicidal activity 3 and 24 hours post inoculation. The therapeutic effects of NAC combination with AMB were investigated in a murine model with daily treatments regimens. NAC alone reduced the oxidative burst generated by AMB in yeast cells, but did not inhibit fungal growth. The combination NAC + AMB decreased capsule size, zeta potential, superoxide dismutase activity and lipid peroxidation. In macrophage assays, NAC + AMB did not influence the phagocytosis, but induced fungal killing with different levels of oxidative bursts when compared to AMB alone: there was an increased reactive oxygen species (ROS) after 3 hours and reduced levels after 24 hours. By contrast, ROS remained elevated when AMB was tested alone, demonstrating that NAC reduced AMB oxidative effects without influencing its antifungal activity. Uninfected mice treated with NAC + AMB had lower concentrations of serum creatinine and glutamate-pyruvate transaminase in comparison to AMB. The combination of NAC + AMB was far better than AMB alone in increasing survival and reducing morbidity in murine-induced cryptococcosis, leading to reduced fungal burden in lungs and brain and also lower concentrations of pro-inflammatory cytokines in the lungs. In conclusion, NAC + AMB may represent an alternative adjuvant for the treatment of cryptococcosis.

PMID: 31919505 [PubMed - as supplied by publisher]

ChemBioServer 2.0: An advanced web server for filtering, clustering and networking of chemical compounds facilitating both drug discovery and repurposing.

Bioinformatics. 2020 Jan 08;:

Authors: Karatzas E, Zamora JE, Athanasiadis E, Dellis D, Cournia Z, Spyrou GM

Abstract
ChemBioServer 2.0 is the advanced sequel of a web-server for filtering, clustering and networking of chemical compound libraries facilitating both drug discovery and repurposing. It provides researchers the ability to (i) browse and visualize compounds along with their physicochemical and toxicity properties, (ii) perform property-based filtering of chemical compounds, (iii) explore compound libraries for lead optimization based on perfect match substructure search, (iv) re-rank virtual screening results to achieve selectivity for a protein of interest against different protein members of the same family, selecting only those compounds that score high for the protein of interest, (v) perform clustering among the compounds based on their physicochemical properties providing representative compounds for each cluster, (vi) construct and visualize a structural similarity network of compounds providing a set of network analysis metrics, (vii) combine a given set of compounds with a reference set of compounds into a single structural similarity network providing the opportunity to infer drug repurposing due to transitivity, (viii) remove compounds from a network based on their similarity with unwanted substances (e.g. failed drugs) and (ix) build custom compound mining pipelines.
AVAILABILITY: http://chembioserver.vi-seem.eu.

PMID: 31913451 [PubMed - as supplied by publisher]