Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles.

EBioMedicine. 2019 Dec 23;:102585

Authors: Malas TB, Leonhard WN, Bange H, Granchi Z, Hettne KM, Van Westen GJP, Price LS, 't Hoen PAC, Peters DJM

Abstract
BACKGROUND: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Tolvaptan, the only drug approved for ADPKD treatment, results in serious side-effects, warranting the need for novel drugs.
METHODS: In this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. We followed an integrative computational approach using a combination of gene expression profiling, bioinformatics and cheminformatics data.
FINDINGS: We identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinically-approved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone. Further testing the efficacy of six candidate drugs for inhibition of cyst swelling using a human 3D-cyst assay, revealed that three of the six had cyst-growth reducing effects with limited toxicity.
INTERPRETATION: Our data further establishes drug repurposing as a robust drug discovery method, with three promising drug candidates identified for ADPKD treatment (Meclofenamic Acid, Gamolenic Acid and Birinapant). Our strategy that combines multiple-omics data, can be extended for ADPKD and other diseases in the future.
FUNDING: European Union's Seventh Framework Program, Dutch Technology Foundation Stichting Technische Wetenschappen and the Dutch Kidney Foundation.

PMID: 31879244 [PubMed - as supplied by publisher]

The antifungal isavuconazole inhibits the entry of lassa virus by targeting the stable signal peptide-GP2 subunit interface of lassa virus glycoprotein.

Antiviral Res. 2019 Dec 23;:104701

Authors: Zhang X, Tang K, Guo Y

Abstract
Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever in humans, and the limited therapeutic treatment for Lassa fever poses significant threat to public health in West Africa. Using an HIV based pseudovirus platform, we identified isavuconazole, a triazole antifungal for systemic use, as a LASV entry inhibitor with an EC50 of 1.2 μM. Isavuconazole inhibits Lassa virus entry by blocking the pH dependent viral fusion mediated by the Lassa virus surface glycoprotein. Fragment replacement mutational study indicated that isavuconazole targets the stable signal peptide (SSP)-membrane fusion subunit (GP2) interface of Lassa glycoprotein. Further mutational study of the SSP-GP2 region of LASV glycoprotein revealed that S27 in the N-terminal transmembrane region of SSP and V431, F434 and V435 in the transmembrane domain of GP2 affect anti-LASV activity of isavuconazole. Isavuconazole also displays antiviral activity to five New World (NW) mammarenaviruses that cause hemorrhagic fever. This study facilitates the potential repurposing of isavuconazole for therapeutic intervention against human-pathogenic arenaviruses, and provides the basis for further structural optimization of arenavirus fusion inhibitors based on the predicted structural characteristics of the unique SSP-GP2 interface.

PMID: 31877348 [PubMed - as supplied by publisher]

Drug Repurposing for Cancer Therapy, Easier Said Than Done.

Semin Cancer Biol. 2019 Dec 23;:

Authors: Gonzalez-Fierro A, Dueñas-González A

Abstract
Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

PMID: 31877340 [PubMed - as supplied by publisher]

Repurposing existing medications in oncology and their potential role in oral cancer.

Oral Dis. 2019 01;25(1):6-9

Authors: Basile JR, Czerninski R

PMID: 29575546 [PubMed - indexed for MEDLINE]

Drug repositioning based on individual bi-random walks on a heterogeneous network.

BMC Bioinformatics. 2019 Dec 24;20(Suppl 15):547

Authors: Wang Y, Guo M, Ren Y, Jia L, Yu G

Abstract
BACKGROUND: Traditional drug research and development is high cost, time-consuming and risky. Computationally identifying new indications for existing drugs, referred as drug repositioning, greatly reduces the cost and attracts ever-increasing research interests. Many network-based methods have been proposed for drug repositioning and most of them apply random walk on a heterogeneous network consisted with disease and drug nodes. However, these methods generally adopt the same walk-length for all nodes, and ignore the different contributions of different nodes.
RESULTS: In this study, we propose a drug repositioning approach based on individual bi-random walks (DR-IBRW) on the heterogeneous network. DR-IBRW firstly quantifies the individual work-length of random walks for each node based on the network topology and knowledge that similar drugs tend to be associated with similar diseases. To account for the inner structural difference of the heterogeneous network, it performs bi-random walks with the quantified walk-lengths, and thus to identify new indications for approved drugs. Empirical study on public datasets shows that DR-IBRW achieves a much better drug repositioning performance than other related competitive methods.
CONCLUSIONS: Using individual random walk-lengths for different nodes of heterogeneous network indeed boosts the repositioning performance. DR-IBRW can be easily generalized to prioritize links between nodes of a network.

PMID: 31874623 [PubMed - in process]

Screening of Natural Extracts for Inhibitors against Japanese Encephalitis Virus Infection.

Antimicrob Agents Chemother. 2019 Dec 23;:

Authors: Guo J, Jia X, Liu Y, Wang S, Cao J, Zhang B, Xiao G, Wang W

Abstract
The mosquito-borne Japanese encephalitis virus (JEV) causes serious illness worldwidely associated with high morbidity and mortality. Currently, there are no effective drugs approved for the treatment of JEV infection. Drug repurposing screen is an alternative approach to discover potential antiviral agents. In this study, high content screening (HCS) of a natural extracts library was performed, and two hit FDA-approved Na+/K+- ATPase inhibitors, ouabain and digoxin, were identified of having robust efficiency against JEV infection with the selectivity indexes over 1000. The results indicated that ouabain and digoxin blocked the JEV infection at the replication stage by targeting the Na+/K+- ATPase. Furthermore, it was proved that ouabain significantly reduced the morbidity and mortality caused by JEV in a BALB/c mouse model. This work demonstrated that Na+/K+- ATPase could be served as the target of treatment of JEV infection, and ouabain has the potential to be developed as an effective anti-JEV drug.

PMID: 31871089 [PubMed - as supplied by publisher]

Overlap matrix completion for predicting drug-associated indications.

PLoS Comput Biol. 2019 Dec 23;15(12):e1007541

Authors: Yang M, Luo H, Li Y, Wu FX, Wang J

Abstract
Identification of potential drug-associated indications is critical for either approved or novel drugs in drug repositioning. Current computational methods based on drug similarity and disease similarity have been developed to predict drug-disease associations. When more reliable drug- or disease-related information becomes available and is integrated, the prediction precision can be continuously improved. However, it is a challenging problem to effectively incorporate multiple types of prior information, representing different characteristics of drugs and diseases, to identify promising drug-disease associations. In this study, we propose an overlap matrix completion (OMC) for bilayer networks (OMC2) and tri-layer networks (OMC3) to predict potential drug-associated indications, respectively. OMC is able to efficiently exploit the underlying low-rank structures of the drug-disease association matrices. In OMC2, first of all, we construct one bilayer network from drug-side aspect and one from disease-side aspect, and then obtain their corresponding block adjacency matrices. We then propose the OMC2 algorithm to fill out the values of the missing entries in these two adjacency matrices, and predict the scores of unknown drug-disease pairs. Moreover, we further extend OMC2 to OMC3 to handle tri-layer networks. Computational experiments on various datasets indicate that our OMC methods can effectively predict the potential drug-disease associations. Compared with the other state-of-the-art approaches, our methods yield higher prediction accuracy in 10-fold cross-validation and de novo experiments. In addition, case studies also confirm the effectiveness of our methods in identifying promising indications for existing drugs in practical applications.

PMID: 31869322 [PubMed - as supplied by publisher]

Metabolic-Pathway-Oriented Screening Targeting S-Adenosyl-l-methionine Reveals the Epigenetic Remodeling Activities of Naturally Occurring Catechols.

J Am Chem Soc. 2019 Dec 23;:

Authors: Ogihara S, Komatsu T, Itoh Y, Miyake Y, Suzuki T, Yanagi K, Kimura Y, Ueno T, Hanaoka K, Kojima H, Okabe T, Nagano T, Urano Y

Abstract
Methyl transfer reactions play important roles in many biological phenomena, wherein the methylation cofactor S-adenosyl-l-methionine (SAM) serves as the important currency to orchestrate those reactions. We have developed a fluorescent-probe-based high-throughput screening (HTS) system to search for the compounds that control cellular SAM levels. HTS with a drug repositioning library revealed the importance of catechol-O-methyltransferase (COMT) and its substrates in controlling the SAM concentrations and histone methylation levels in colorectal tumor cells.

PMID: 31869215 [PubMed - as supplied by publisher]

Identification of novel compounds against Tat-mediated human immunodeficiency virus-1 transcription by high-throughput functional screening assay.

Biochem Biophys Res Commun. 2019 Dec 19;:

Authors: Shin Y, Kim HG, Park CM, Choi MS, Kim DE, Choi BS, Kim K, Yoon CH

Abstract
Trans-activator (Tat)-mediated human immunodeficiency virus type 1 (HIV-1) transcription is essential for the replication of HIV-1 and is considered a potent therapeutic target for HIV-1 inhibition. In this study, the Library of Pharmacologically Active Compounds (LOPAC1280) was screened using our dual-reporter screening system for repositioning as Tat-inhibitory compounds. Consequently, two compounds were found to be potent, with low cytotoxicity. Of these two compounds, Roscovitine (CYC202) is already known to be a Tat inhibitor, while gemcitabine has been newly identified as an inhibitor of Tat-mediated transcription linked to viral production and replication. In an additional screening using the ribonucleoside analogues of gemcitabine, two analogues (2'-C-methylcytidine and 3-deazauridine) showed a specific Tat-inhibitory effect linked to their anti-HIV-1 activity. Interestingly, these compounds did not affect Tat protein directly, while the mechanism underlying their inhibition of Tat-mediated transcription was linked to pyrimidine biosynthesis, rather than to alteration of the dNTP pool, influenced by the inhibition of ribonucleotide reductase. Taken together, the proposed functional screening system is a useful tool for the identification of inhibitors of Tat-mediated HIV-1 transcription from among a large number of compounds, and the inhibitory effect of HIV-1 transcription by gemcitabine and its analogues may suggest a strategy for developing a new class of therapeutic anti-HIV drugs.

PMID: 31866007 [PubMed - as supplied by publisher]

Repurposing bioactive aporphine alkaloids as efflux pump inhibitors.

Fitoterapia. 2019 Nov;139:104371

Authors: Avci FG, Atas B, Aksoy CS, Kurpejovic E, Gulsoy Toplan G, Gurer C, Guillerminet M, Orelle C, Jault JM, Sariyar Akbulut B

Abstract
Extrusion of drugs or drug-like compounds through bacterial efflux pumps is a serious health issue that leads to loss in drug efficacy. Combinatorial therapies of low-efficacy drugs with efflux pump inhibitors may help to restore the activities of such drugs. In this quest, natural products are attractive molecules, since in addition to their wide range of bioactivities they may inhibit efflux pumps. The current work repurposed the bioactive alkaloid roemerine as a potential efflux pump inhibitor. In Bacillus subtilis, both Bmr and BmrA, belonging to the major facilitator and the ATP-binding cassette superfamilies, respectively, were found to be inhibited by roemerine. Scanning electron microscopy and RNA-Seq analyses showed that it potentiated the effect of berberine. Growth rates and checkerboard assays confirmed the synergy of roemerine and berberine and that roemerine prevented berberine efflux by inhibiting Bmr. Transport assays with inverted membrane vesicles prepared from Escherichia coli overexpressing BmrA showed that increasing roemerine concentration decreased the transport of doxorubicin, the BmrA substrate, confirming that roemerine may also be considered as an inhibitor of BmrA. Thus, these findings suggest that conjugation of roemerine to substrates of efflux pumps, Bmr and BmrA, may help to potentiate the activity of their drug substrates.

PMID: 31629051 [PubMed - indexed for MEDLINE]

Fingolimod sensitizes EGFR wild‑type non‑small cell lung cancer cells to lapatinib or sorafenib and induces cell cycle arrest.

Oncol Rep. 2019 Jul;42(1):231-242

Authors: Ota K, Okuma T, Lorenzo A, Yokota A, Hino H, Kazama H, Moriya S, Takano N, Hiramoto M, Miyazawa K

Abstract
Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase and mutations in this gene are major drivers of lung cancer development. EGFR tyrosine kinase inhibitors (TKIs) are standard first‑line therapies for patients with advanced non‑small cell lung cancer (NSCLC) with activating EGFR mutations, but are not effective in patients with wild‑type EGFR. In the present study, the cytotoxic effects of various TKIs against EGFR were investigated in wild‑type NSCLC cells as single treatments or in combination with Fingolimod (FTY720), which has been approved for treating multiple sclerosis and has cytotoxic effects against several tumor cell lines. It was found that the combined treatment with TKIs lapatinib (Lap) or sorafenib (Sor) and FTY720 synergistically suppressed the viability of the NSCLC cell lines A549 and H596. Additionally, FTY720 inhibited lysosomal acidification and suppressed autophagy flux. Immunoblotting and reverse transcription‑quantitative polymerase chain reaction showed that FTY720 combined with Lap or Sor, enhanced endoplasmic reticulum (ER) stress loading and cell cycle arrest in A549 cells. The enhancement of ER stress loading and cell cycle arrest induced by combined treatment with Lap or Sor and FTY720, which was associated with the cytotoxicity induced by the combination of these drugs. These findings suggested that FTY720 improved TKI therapy in NSCLC patients with wild‑type EGFR, by sensitizing NSCLC cells to TKIs.

PMID: 31059070 [PubMed - indexed for MEDLINE]

Current trends in the pharmacological management of Chagas disease.

Int J Parasitol Drugs Drug Resist. 2019 Dec 10;12:7-17

Authors: Ribeiro V, Dias N, Paiva T, Hagström-Bex L, Nitz N, Pratesi R, Hecht M

Abstract
Chagas disease (CD) is a tropical neglected illness, affecting mainly populations of low socioeconomic status in Latin America. An estimated 6 to 8 million people worldwide are infected with Trypanosoma cruzi, the etiological agent of CD. Despite being one of the main global health problems, this disease continues without effective treatment during the chronic phase of the infection. The limitation of therapeutic strategies has been one of the biggest challenges on the fight against CD. Nifurtimox and benznidazole, developed in the 1970s, are still the only commercial options with established efficacy on CD. However, the efficacy of these drugs have a proven efficacy only during early infection and the benefits in the chronic phase are questionable. Consequently, there is a growing need for new pharmacological alternatives, either by optimization of existing drugs or by the formulation of new compounds. In the present study, a literature review of the currently adopted therapy, its concomitant combination with other drugs, and potential future treatments for CD was performed, considering articles published from 2012. The revised articles were selected according to the protocol of treatment: evaluation of drug association, drug repositioning and research of new drugs. As a result of the present revision, it was possible to conclude that the use of benznidazole in combination with other compounds showed better results when compared with its use as a single therapy. The search of new drugs has been the strategy most used in pursuing more effective forms of treatment for CD. However, studies have still focused on basic research, that is, they are still in a pre-clinical stage, using methodologies based on in vitro or in animal studies.

PMID: 31862616 [PubMed - as supplied by publisher]

The Thrombopoietin Receptor Agonist Eltrombopag Inhibits Human Cytomegalovirus Replication Via Iron Chelation.

Cells. 2019 Dec 20;9(1):

Authors: Vogel JU, Schmidt S, Schmidt D, Rothweiler F, Koch B, Baer P, Rabenau H, Michel D, Stamminger T, Michaelis M, Cinatl J

Abstract
The thrombopoietin receptor agonist eltrombopag was successfully used against human cytomegalovirus (HCMV)-associated thrombocytopenia refractory to immunomodulatory and antiviral drugs. These effects were ascribed to the effects of eltrombopag on megakaryocytes. Here, we tested whether eltrombopag may also exert direct antiviral effects. Therapeutic eltrombopag concentrations inhibited HCMV replication in human fibroblasts and adult mesenchymal stem cells infected with six different virus strains and drug-resistant clinical isolates. Eltrombopag also synergistically increased the anti-HCMV activity of the mainstay drug ganciclovir. Time-of-addition experiments suggested that eltrombopag interfered with HCMV replication after virus entry. Eltrombopag was effective in thrombopoietin receptor-negative cells, and the addition of Fe3+ prevented the anti-HCMV effects, indicating that it inhibits HCMV replication via iron chelation. This may be of particular interest for the treatment of cytopenias after hematopoietic stem cell transplantation, as HCMV reactivation is a major reason for transplantation failure. Since therapeutic eltrombopag concentrations are effective against drug-resistant viruses, and synergistically increase the effects of ganciclovir, eltrombopag is also a drug-repurposing candidate for the treatment of therapy-refractory HCMV disease.

PMID: 31861948 [PubMed - in process]

The Role of Drug Repurposing in the Development of Novel Antimicrobial Drugs: Non-Antibiotic Pharmacological Agents as Quorum Sensing-Inhibitors.

Antibiotics (Basel). 2019 Dec 17;8(4):

Authors: Gajdács M, Spengler G

Abstract
Background: The emergence of multidrug-resistant organisms (MDROs) is a global public health issue, severely hindering clinicians in administering appropriate antimicrobial therapy. Drug repurposing is a drug development strategy, during which new pharmacological applications are identified for already approved drugs. From the viewpoint of the development of virulence inhibitors, inhibition of quorum sensing (QS) is a promising route because various important features in bacterial physiology and virulence are mediated by QS-dependent gene expression. Methods: Forty-five pharmacological agents, encompassing a wide variety of different chemical structures and mechanisms of action, were tested during our experiments. The antibacterial activity of the compounds was tested using the broth microdilution method. Screening and semi-quantitative assessment of QS-inhibition by the compounds was performed using QS-signal molecule-producing and indicator strains. Results: Fourteen pharmaceutical agents showed antibacterial activity in the tested concentration range, while eight drugs (namely 5-fluorouracil, metamizole-sodium, cisplatin, methotrexate, bleomycin, promethazine, chlorpromazine, and thioridazine) showed dose-dependent QS-inhibitory activity in the in vitro model systems applied during the experiments. Conclusions: Virulence inhibitors represent an attractive alternative strategy to combat bacterial pathogens more efficiently. Some of the tested compounds could be considered potential QS-inhibitory agents, warranting further experiments involving additional model systems to establish the extent of their efficacy.

PMID: 31861228 [PubMed]

The Benzimidazole-Based Anthelmintic Parbendazole: A Repurposed Drug Candidate That Synergizes with Gemcitabine in Pancreatic Cancer.

Cancers (Basel). 2019 Dec 17;11(12):

Authors: Florio R, Veschi S, di Giacomo V, Pagotto S, Carradori S, Verginelli F, Cirilli R, Casulli A, Grassadonia A, Tinari N, Cataldi A, Amoroso R, Cama A, De Lellis L

Abstract
Pancreatic cancer (PC) is one of the most lethal, chemoresistant malignancies and it is of paramount importance to find more effective therapeutic agents. Repurposing of non-anticancer drugs may expand the repertoire of effective molecules. Studies on repurposing of benzimidazole-based anthelmintics in PC and on their interaction with agents approved for PC therapy are lacking. We analyzed the effects of four Food and Drug Administration (FDA)-approved benzimidazoles on AsPC-1 and Capan-2 pancreatic cancer cell line viability. Notably, parbendazole was the most potent benzimidazole affecting PC cell viability, with half maximal inhibitory concentration (IC50) values in the nanomolar range. The drug markedly inhibited proliferation, clonogenicity and migration of PC cell lines through mechanisms involving alteration of microtubule organization and formation of irregular mitotic spindles. Moreover, parbendazole interfered with cell cycle progression promoting G2/M arrest, followed by the emergence of enlarged, polyploid cells. These abnormalities, suggesting a mitotic catastrophe, culminated in PC cell apoptosis, are also associated with DNA damage in PC cell lines. Remarkably, combinations of parbendazole with gemcitabine, a drug employed as first-line treatment in PC, synergistically decreased PC cell viability. In conclusion, this is the first study providing evidence that parbendazole as a single agent, or in combination with gemcitabine, is a repurposing candidate in the currently dismal PC therapy.

PMID: 31861153 [PubMed]

Repurposing drugs for skin cancer.

Curr Med Chem. 2019 Dec 19;:

Authors: Khachigian LM

Abstract
Drug repurposing, put simply, is the process of developing existing or abandoned drugs for a different disease. Repurposing can circumvent higher costs and times associated with conventional drug discovery strategies because toxicity and pharmacokinetics profiles are typically already established. This brief review focuses on efforts to repurpose drugs for skin cancer and includes the reuse of antihypertensives, anthelmintics and antifungals among a range of other medicines. Repurposing not only ushers promising known drugs for new indications, the process of repurposing can uncover new mechanistic insights in the pathogenesis of disease and uncover new opportunities for pharmaceutical intervention.

PMID: 31858902 [PubMed - as supplied by publisher]

Biological Functions and Molecular Mechanisms of Antibiotic Tigecycline in the Treatment of Cancers.

Int J Mol Sci. 2019 Jul 22;20(14):

Authors: Dong Z, Abbas MN, Kausar S, Yang J, Li L, Tan L, Cui H

Abstract
As an FDA-approved drug, glycylcycline tigecycline has been used to treat complicated microbial infections. However, recent studies in multiple hematologic and malignant solid tumors reveal that tigecycline treatment induces cell cycle arrest, apoptosis, autophagy and oxidative stress. In addition, tigecycline also inhibits mitochondrial oxidative phosphorylation, cell proliferation, migration, invasion and angiogenesis. Importantly, combinations of tigecycline with chemotherapeutic or targeted drugs such as venetoclax, doxorubicin, vincristine, paclitaxel, cisplatin, and imatinib, have shown to be promising strategies for cancer treatment. Mechanism of action studies reveal that tigecycline leads to the inhibition of mitochondrial translation possibly through interacting with mitochondrial ribosome. Meanwhile, this drug also interferes with several other cell pathways/targets including MYC, HIFs, PI3K/AKT or AMPK-mediated mTOR, cytoplasmic p21 CIP1/Waf1, and Wnt/β-catenin signaling. These evidences indicate that antibiotic tigecycline is a promising drug for cancer treatment alone or in combination with other anticancer drugs. This review summarizes the biological function of tigecycline in the treatment of tumors and comprehensively discusses its mode of action.

PMID: 31336613 [PubMed - indexed for MEDLINE]

Repurposing a polymer precursor: Synthesis and in vitro medicinal potential of ferrocenyl 1,3-benzoxazine derivatives.

Eur J Med Chem. 2019 Dec 02;187:111924

Authors: Mbaba M, Dingle LMK, Cash D, Mare JA, Laming D, Taylor D, Hoppe HC, Edkins AL, Khanye SD

Abstract
Cancer and malaria remain relevant pathologies in modern medicinal chemistry endeavours. This is compounded by the threat of development of resistance to existing clinical drugs in use as first-line option for treatment of these diseases. To counter this threat, strategies such as drug repurposing and hybridization are constantly adapted in contemporary drug discovery for the expansion of the drug arsenal and generation of novel chemotypes with potential to avert or delay resistance. In the present study, a polymer precursor scaffold, 1,3-benzoxazine, has been repurposed by incorporation of an organometallic ferrocene unit to produce a novel class of compounds showing in vitro biological activity against breast cancer, malaria and trypanosomiasis. The resultant ferrocenyl 1,3-benzoxazine compounds displayed high potency and selectivity against the investigated diseases, with IC50 values in the low and sub-micromolar range against both chloroquine-sensitive (3D7) and resistant (Dd2) strains of the Plasmodium falciparum parasite. On the other hand, antitrypanosomal (Trypanosoma brucei brucei) potencies were observed between 0.15 and 38.6 μM. The majority of the compounds were not active against breast cancer cells (HCC70), however, for the toxic compounds, IC50 values ranged from 11.0 to 30.5 μM. Preliminary structure-activity relationships revealed the basic oxazine sub-ring and lipophilic benzene substituents to be conducive for biological efficacy of the ferrocenyl 1,3-benzoxazines reported in the study. DNA interaction studies performed on the most promising compound 4c suggested that DNA damage may be one possible mode of action of this class of compounds.

PMID: 31855792 [PubMed - as supplied by publisher]

Synergistic combinations of anthelmintic salicylanilides oxyclozanide, rafoxanide, and closantel with colistin eradicates multidrug-resistant colistin-resistant Gram-negative bacilli.

J Antibiot (Tokyo). 2019 08;72(8):605-616

Authors: Domalaon R, Okunnu O, Zhanel GG, Schweizer F

Abstract
Repurposing nonantibiotic drugs for antimicrobial therapy presents a viable approach to drug discovery. Development of therapeutic strategies that overcome existing resistance mechanisms is important especially against those bacterial infections in which treatment options are limited, such as against multidrug-resistant Gram-negative bacilli. Herein, we provide in vitro data that suggest the addition of anthelmintic salicylanilides, including oxyclozanide, rafoxanide, and closantel, in colistin therapy to treat multidrug-resistant colistin-susceptible but more importantly colistin-resistant Gram-negative bacilli. As a stand-alone agent, the three salicylanilides suffered from limited outer membrane permeation in Pseudomonas aeruginosa, with oxyclozanide also susceptible to efflux. Synergy was apparent for the combinations against multidrug-resistant clinical isolates of P. aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Enterobacter cloacae. Susceptibility breakpoints for colistin, but also with polymyxin B, were reached upon addition of 1 µg ml-1 of the corresponding salicylanilide against colistin-resistant Gram-negative bacilli. Furthermore, enhanced bacterial killing was observed in all combinations. Our data corroborate the repositioning of the three salicylanilides as adjuvants to counter resistance to the antibiotic of last resort colistin. Our findings are timely and relevant since the global dissemination of plasmid-mediated colistin resistance had been realized.

PMID: 31028351 [PubMed - indexed for MEDLINE]

Identification of Zika virus NS2B-NS3 protease inhibitors by Structure-Based Virtual Screening and Drug Repurposing Approaches.

J Chem Inf Model. 2019 Dec 18;:

Authors: Santos F, Nunes DAF, Lima WG, Davyt D, Santos LL, Taranto AG, Maria Siqueira Ferreira J

Abstract
The NS2B-NS3 protease has been identified as an attractive target for drug development against Zika virus (ZIKV) and combined drug repurposing and structure-based virtual screening has improved the development of antiviral drugs. In this study, we performed a structure-based virtual screening of 1861 Food and Administration (FDA) approved drugs available in DrugBank by the selection and docking validation of crystal structure of ZIKV NS2B-NS3 protease (PDB ID 5H4I) using Glide and DOCK 6 software. The antihistaminic chlorcyclizine (Grid score -24.8 Kcal/mol) exhibited the most promising interaction with NS2B-NS3 protease in comparison to crystallography ligand (Grid score -15.6 kcal/mol) by interaction to Tyr161 by hydrophobic interactions in the binding site of NS2B-NS3 which is recognized as an important aminoacid in substrate molecular recognition. Cytotoxicity and global antiviral activity assay in vero cells by MTT method showed that chlorcyclizine reduced the ZIKV induced cytopathic effect (EC50 of 69.0 ± 7.3 µM and SI = 1.9) and explicit molecular dynamics simulations implemented on an NAMD program indicated great stability of chlorcyclizine in protease binding site, suggesting the repurposing of chlorcyclizine as a promising finding in anti-ZIKV drugs development.

PMID: 31850756 [PubMed - as supplied by publisher]