A Repurposing Approach for Uncovering the Anti-Tubercular Activity of FDA-Approved Drugs with Potential Multi-Targeting Profiles.

Molecules. 2019 Nov 29;24(23):

Authors: Battah B, Chemi G, Butini S, Campiani G, Brogi S, Delogu G, Gemma S

Abstract
Tuberculosis (TB) is one of the top 10 causes of death worldwide. This scenario is further complicated by the insurgence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. The identification of appropriate drugs with multi-target affinity profiles is considered to be a widely accepted strategy to overcome the rapid development of resistance. The aim of this study was to discover Food and Drug Administration (FDA)-approved drugs possessing antimycobacterial activity, potentially coupled to an effective multi-target profile. An integrated screening platform was implemented based on computational procedures (high-throughput docking techniques on the target enzymes peptide deformylase and Zmp1) and in vitro phenotypic screening assays using two models to evaluate the activity of the selected drugs against Mycobacterium tuberculosis (Mtb), namely, growth of Mtb H37Rv and of two clinical isolates in axenic media, and infection of peripheral blood mononuclear cells with Mtb. Starting from over 3000 FDA-approved drugs, we selected 29 marketed drugs for submission to biological evaluation. Out of 29 drugs selected, 20 showed antimycobacterial activity. Further characterization suggested that five drugs possessed promising profiles for further studies. Following a repurposing strategy, by combining computational and biological efforts, we identified marketed drugs with relevant antimycobacterial profiles.

PMID: 31795400 [PubMed - in process]

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CYCLOSERINE ENANTIOMERS ARE REVERSIBLE INHIBITORS OF HUMAN ALANINE:GLYOXYLATE AMINOTRANSFERASE: IMPLICATIONS FOR PRIMARY HYPEROXALURIA TYPE 1.

Biochem J. 2019 Dec 03;:

Authors: Dindo M, Grottelli S, Annunziato G, Giardina G, Pieroni M, Pampalone G, Faccini A, Cutruzzolà F, Laurino P, Costantino G, Cellini B

Abstract
Peroxisomal alanine:glyoxylate aminotransferase (AGT) is responsible for glyoxylate detoxification in human liver and utilizes pyridoxal 5'-phosphate (PLP) as coenzyme. The deficit of AGT leads to Primary Hyperoxaluria Type I (PH1), a rare disease characterized by calcium oxalate stones deposition in the urinary tract as a consequence of glyoxylate accumulation. Most missense mutations cause AGT misfolding, as in the case of the G41R, which induces aggregation and proteolytic degradation. We have investigated the interaction of wild-type AGT and the pathogenic G41R variant with D-cycloserine (DCS, commercialized as Seromycin), a natural product used as a second-line treatment of multidrug-resistant tuberculosis, and its synthetic enantiomer L-cycloserine (LCS). In contrast with evidences previously reported on other PLP-enzymes, both ligands are AGT reversible inhibitors showing inhibition constants in the micromolar range. While LCS undergoes half-transamination generating a ketimine intermediate and behaves as a classical competitive inhibitor, DCS displays a time-dependent binding mainly generating an oxime intermediate. Using a mammalian cellular model, we found that DCS, but not LCS, is able to promote the correct folding of the G41R variant, as revealed by its increased specific activity and expression as soluble protein. This effect also translates into an increased glyoxylate detoxification ability of cells expressing the variant upon treatment with DCS. Overall, our findings establish that DCS could play a role as pharmacological chaperone, thus suggesting a new line of intervention against PH1 based on a drug repositioning approach. To a widest extent, this strategy could be applied to other disease-causing mutations leading to AGT misfolding.

PMID: 31794008 [PubMed - as supplied by publisher]

Blood biomarkers for memory: toward early detection of risk for Alzheimer disease, pharmacogenomics, and repurposed drugs.

Mol Psychiatry. 2019 Dec 02;:

Authors: Niculescu AB, Le-Niculescu H, Roseberry K, Wang S, Hart J, Kaur A, Robertson H, Jones T, Strasburger A, Williams A, Kurian SM, Lamb B, Shekhar A, Lahiri DK, Saykin AJ

Abstract
Short-term memory dysfunction is a key early feature of Alzheimer's disease (AD). Psychiatric patients may be at higher risk for memory dysfunction and subsequent AD due to the negative effects of stress and depression on the brain. We carried out longitudinal within-subject studies in male and female psychiatric patients to discover blood gene expression biomarkers that track short term memory as measured by the retention measure in the Hopkins Verbal Learning Test. These biomarkers were subsequently prioritized with a convergent functional genomics approach using previous evidence in the field implicating them in AD. The top candidate biomarkers were then tested in an independent cohort for ability to predict state short-term memory, and trait future positive neuropsychological testing for cognitive impairment. The best overall evidence was for a series of new, as well as some previously known genes, which are now newly shown to have functional evidence in humans as blood biomarkers: RAB7A, NPC2, TGFB1, GAP43, ARSB, PER1, GUSB, and MAPT. Additional top blood biomarkers include GSK3B, PTGS2, APOE, BACE1, PSEN1, and TREM2, well known genes implicated in AD by previous brain and genetic studies, in humans and animal models, which serve as reassuring de facto positive controls for our whole-genome gene expression discovery approach. Biological pathway analyses implicate LXR/RXR activation, neuroinflammation, atherosclerosis signaling, and amyloid processing. Co-directionality of expression data provide new mechanistic insights that are consistent with a compensatory/scarring scenario for brain pathological changes. A majority of top biomarkers also have evidence for involvement in other psychiatric disorders, particularly stress, providing a molecular basis for clinical co-morbidity and for stress as an early precipitant/risk factor. Some of them are modulated by existing drugs, such as antidepressants, lithium and omega-3 fatty acids. Other drug and nutraceutical leads were identified through bioinformatic drug repurposing analyses (such as pioglitazone, levonorgestrel, salsolidine, ginkgolide A, and icariin). Our work contributes to the overall pathophysiological understanding of memory disorders and AD. It also opens new avenues for precision medicine- diagnostics (assement of risk) as well as early treatment (pharmacogenomically informed, personalized, and preventive).

PMID: 31792364 [PubMed - as supplied by publisher]

DRUG REPURPOSING-Overcoming the translational hurdles to clinical use.

Pharmacol Res Perspect. 2019 Dec;7(6):e00548

Authors: Martin JH, Bowden NA

PMID: 31788319 [PubMed - in process]

A new pragmatic design for dose escalation in phase 1 clinical trials using an adaptive continual reassessment method.

BMC Cancer. 2019 Jun 26;19(1):632

Authors: North B, Kocher HM, Sasieni P

Abstract
BACKGROUND: A key challenge in phase I trials is maintaining rapid escalation in order to avoid exposing too many patients to sub-therapeutic doses, while preserving safety by limiting the frequency of toxic events. Traditional rule-based designs require temporarily stopping recruitment whilst waiting to see whether enrolled patients develop toxicity. This can be both inefficient and introduces logistic challenges to recruitment in the clinic. We describe a novel two-stage dose assignment procedure designed for a phase I clinical trial (STARPAC), where a good estimation of prior was possible.
METHODS: The STARPAC design uses rule-based design until the first patient has a dose limiting toxicity (DLT) and then switches to a modified CRM, with rules to handle patient recruitment during follow-up of earlier patients. STARPAC design is compared via simulations with the TITE-CRM and 3 + 3 methods in various toxicity estimate (T1-5), rate of recruitment (R1-2), and DLT events timing (DT1-4), scenarios using several metrics: accuracy of maximum tolerated dose (MTD), numbers of DLTs, number of patients enrolled and those missed; duration of trial; and proportion of patients treated at the therapeutic dose or MTD.
RESULTS: The simulations suggest that STARPAC design performed well in MTD estimation and in treating patients at the highest possible therapeutic levels. STARPAC and TITE-CRM were comparable in the number of patients required and DLTs incurred. The 3 + 3 design often had fewer patients and DLTs although this is due to its low escalation rate leading to poor MTD estimation. For the numbers of declined patients and MTD estimation 3 + 3 is uniformly worse, with STARPAC being better in those metrics for high toxicity scenarios and TITE-CRM better with low toxicity. In situations including doses with toxicities both above and below 30%, the STARPAC design outperformed TITE-CRM with respect to every metric.
CONCLUSION: When considering doses with toxicities both above and below the target of 30% toxicities, the two-stage STARPAC dose escalation design provides a more efficient phase I trial design than either the traditional 3 + 3 or the TITE-CRM design. Trialists should model various designs via simulation to adopt the most efficient design for their clinical scenario.
TRIAL REGISTRATION: Clinical Trials NCT03307148 (11 October 2017).

PMID: 31242873 [PubMed - indexed for MEDLINE]

Ivermectin reverses the drug resistance in cancer cells through EGFR/ERK/Akt/NF-κB pathway.

J Exp Clin Cancer Res. 2019 Jun 18;38(1):265

Authors: Jiang L, Wang P, Sun YJ, Wu YJ

Abstract
BACKGROUND: Discovery and development of novel drugs that are capable of overcoming drug resistance in tumor cells are urgently needed clinically. In this study, we sought to explore whether ivermectin (IVM), a macrolide antiparasitic agent, could overcome the resistance of cancer cells to the therapeutic drugs.
METHODS: We used two solid tumor cell lines (HCT-8 colorectal cancer cells and MCF-7 breast cancer cells) and one hematologic tumor cell line (K562 chronic myeloid leukemia cells), which are resistant to the chemotherapeutic drugs vincristine and adriamycin respectively, and two xenograft mice models, including the solid tumor model in nude mice with the resistant HCT-8 cells and the leukemia model in NOD/SCID mice with the resistant K562 cells to investigate the reversal effect of IVM on the resistance in vitro and in vivo. MTT assay was used to investigate the effect of IVM on cancer cells growth in vitro. Flow cytometry, immunohistochemistry, and immunofluorescence were performed to investigate the reversal effect of IVM in vivo. Western blotting, qPCR, luciferase reporter assay and ChIP assay were used to detect the molecular mechanism of the reversal effect. Octet RED96 system and Co-IP were used to determine the interactions between IVM and EGFR.
RESULTS: Our results indicated that ivermectin at its very low dose, which did not induce obvious cytotoxicity, drastically reversed the resistance of the tumor cells to the chemotherapeutic drugs both in vitro and in vivo. Mechanistically, ivermectin reversed the resistance mainly by reducing the expression of P-glycoprotein (P-gp) via inhibiting the epidermal growth factor receptor (EGFR), not by directly inhibiting P-gp activity. Ivermectin bound with the extracellular domain of EGFR, which inhibited the activation of EGFR and its downstream signaling cascade ERK/Akt/NF-κB. The inhibition of the transcriptional factor NF-κB led to the reduced P-gp transcription.
CONCLUSIONS: These findings demonstrated that ivermectin significantly enhanced the anti-cancer efficacy of chemotherapeutic drugs to tumor cells, especially in the drug-resistant cells. Thus, ivermectin, a FDA-approved antiparasitic drug, could potentially be used in combination with chemotherapeutic agents to treat cancers and in particular, the drug-resistant cancers.

PMID: 31215501 [PubMed - indexed for MEDLINE]

In silico drug repurposing for the identification of potential candidate molecules against arboviruses infection.

Antiviral Res. 2019 Nov 28;:104668

Authors: Montes-Grajales D, Puerta-Guardo H, Espinosa DA, Harris E, Caicedo-Torres W, Olivero-Verbel J, Martínez-Romero E

Abstract
Arboviral diseases caused by dengue (DENV), Zika (ZIKV) and chikungunya (CHIKV) viruses represent a major public health problem worldwide, especially in tropical areas where millions of infections occur every year. The aim of this research was to identify candidate molecules for the treatment of these diseases among the drugs currently available in the market, through in silico screening and subsequent in vitro evaluation with cell culture models of DENV and ZIKV infections. Numerous pharmaceutical compounds from antibiotics to chemotherapeutic agents presented high in silico binding affinity for the viral proteins, including ergotamine, antrafenine, natamycin, pranlukast, nilotinib, itraconazole, conivaptan and novobiocin. These five last compounds were tested in vitro, being pranlukast the one that exhibited the best antiviral activity. Further In vitro assays for this compound showed a significant inhibitory effect on DENV and ZIKV infection of human monocytic cells and human hepatocytes (Huh-7 cells) with potential abrogation of virus entry. Finally, intrinsic fluorescence analyses suggest that pranlukast may have some level of interaction with three viral proteins of DENV: envelope, capsid, and NS1. Due to its promising results, suitable accessibility in the market and reduced restrictions compared to other pharmaceuticals; the anti-asthmatic pranlukast is proposed as a drug candidate against DENV, ZIKV, and CHIKV, supporting further in vitro and in vivo assessment of the potential of this and other lead compounds that exhibited good affinity scores in silico as therapeutic agents or scaffolds for the development of new drugs against arboviral diseases.

PMID: 31786251 [PubMed - as supplied by publisher]

Screening of FDA approved drugs for finding potential inhibitors against Granzyme B as a potent drug-repurposing target.

J Mol Graph Model. 2019 Oct 11;:107462

Authors: Ikram S, Ahmad J, Durdagi S

Abstract
Granzyme B is one of the best-characterized and extensively studied member of cytotoxic lymphocytes (CL) proteases. Initially, it is thought to be involved in eliminating virally infected or cancerous cells by using a specialized mechanism through which they are internalized into target cells. In the last decade, however this dimension has changed as there are several reports show that not only CL but also other immune cells can also synthesize Granzyme B. This leads to the possibility of the presence of these proteases in extracellular environment. Being active protease, it then raises the possibility of damaging host tissues as evident from the available reported literature. In many instances, Granzyme B is directly involved in pathogenicity, however in others, it contributes to the disease severity as their over expression makes the clinical situation quite worse which ultimately leads to the chronic state of the disease. Serine protease inhibitor-9 is a natural known intracellular inhibitor of Granzyme B, however there is less data available about the potential inhibitors that can regulate its activity in an extracellular environment. Current study is an effort to identify potential novel inhibitors of Granzyme B. For this aim, drug repurposing study was performed. Around 7900 FDA approved drugs were screened using both ligand- and target-driven approaches. Initially, all molecules were docked using induced fit docking (IFD) approach and selected 318 high-docking scored molecules were used in short (1-ns) molecular dynamics (MD) simulations. Based on MM/GBSA binding free energy calculations, 6 compounds were selected and used in long (100-ns) MD simulations. These compounds were then used in binary QSAR analysis. Therapeutic activity potentials of studied compounds were investigated by Clarivate Analytics's MetaCore/MetaDrug platform which uses binary QSAR models. It is developed based on manually curated database of molecular interactions, molecular pathways, gene-disease associations, chemical metabolism and toxicity information. Results of selected compounds were compared with a positive control molecule. Current drug repurposing study is a step ahead in finding potential lead compounds by screening database of FDA approved molecules. We have identified novel inhibitors (Tannic acid, Mupirocin, Phytonadiol sodium diphosphate, Cefpiramide, Xenazoic acid) that have potential to decrease the activity of Granzyme B.

PMID: 31786094 [PubMed - as supplied by publisher]

Artificial Intelligence (AI) in Rare Diseases: Is the Future Brighter?

Genes (Basel). 2019 Nov 27;10(12):

Authors: Brasil S, Pascoal C, Francisco R, Dos Reis Ferreira V, Videira PA, Valadão AG

Abstract
The amount of data collected and managed in (bio)medicine is ever-increasing. Thus, there is a need to rapidly and efficiently collect, analyze, and characterize all this information. Artificial intelligence (AI), with an emphasis on deep learning, holds great promise in this area and is already being successfully applied to basic research, diagnosis, drug discovery, and clinical trials. Rare diseases (RDs), which are severely underrepresented in basic and clinical research, can particularly benefit from AI technologies. Of the more than 7000 RDs described worldwide, only 5% have a treatment. The ability of AI technologies to integrate and analyze data from different sources (e.g., multi-omics, patient registries, and so on) can be used to overcome RDs' challenges (e.g., low diagnostic rates, reduced number of patients, geographical dispersion, and so on). Ultimately, RDs' AI-mediated knowledge could significantly boost therapy development. Presently, there are AI approaches being used in RDs and this review aims to collect and summarize these advances. A section dedicated to congenital disorders of glycosylation (CDG), a particular group of orphan RDs that can serve as a potential study model for other common diseases and RDs, has also been included.

PMID: 31783696 [PubMed - in process]

Dissecting pharmacological effects of Chloroquine in cancer treatment: interference with inflammatory signaling pathways.

Immunology. 2019 Nov 28;:

Authors: Varisli L, Cen O, Vlahopoulos S

Abstract
Chloroquines are 4-aminoquinoline based drugs mainly used to treat malaria. At pharmacological concentrations they have significant effects on tissue homeostasis, targeting diverse signaling pathways in mammalian cells. A key target pathway is autophagy, which regulates macromolecule turnover in the cell. In addition to affecting cellular metabolism and bioenergetic flow equilibrium, autophagy plays a pivotal role at the interface between inflammation and cancer progression. Chloroquines consequently have critical effects in tissue metabolic activity and importantly, in key functions of the immune system. In this article we will review the work addressing the role of chloroquines in the homeostasis of mammalian tissue, and the potential strengths and weaknesses concerning their use in cancer therapy.

PMID: 31782148 [PubMed - as supplied by publisher]

Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing.

Front Med (Lausanne). 2019;6:256

Authors: Reigada C, Sayé M, Phanstiel O, Valera-Vera E, Miranda MR, Pereira CA

Abstract
Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine, and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a high trypanocidal activity against T. cruzi amastigotes (IC50 values of 3.8, 1.9, and 2.9 μM, respectively) and trypomastigotes (IC50 values of 3.4, 2.7, and 1.3 μM, respectively) while in epimastigotes the IC50 were significantly higher (34.7, 41.4, and 39.7 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.

PMID: 31781568 [PubMed]

Search for Therapeutic Agents for Cardiac Arrest Using a Drug Discovery Tool and Large-Scale Medical Information Database.

Front Pharmacol. 2019;10:1257

Authors: Zamami Y, Niimura T, Koyama T, Shigemi Y, Izawa-Ishizawa Y, Morita M, Ohshima A, Harada K, Imai T, Hagiwara H, Okada N, Goda M, Takechi K, Chuma M, Kondo Y, Tsuchiya K, Hinotsu S, Kano MR, Ishizawa K

Abstract
The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using "TargetMine," a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the "survival discharge." Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

PMID: 31780928 [PubMed]

Towards the network-based prediction of repurposed drugs using patient-specific metabolic models.

EBioMedicine. 2019 May;43:26-27

Authors: Pacheco MP, Bintener T, Sauter T

PMID: 30979684 [PubMed - indexed for MEDLINE]

A Prospective Repurposing of Dantrolene as a Multitarget Agent for Alzheimer's Disease.

Molecules. 2019 Nov 25;24(23):

Authors: Bolognino I, Giangregorio N, Pisani L, de Candia M, Purgatorio R, Tonazzi A, Altomare CD, Cellamare S, Catto M

Abstract
The orphan drug dantrolene (DAN) is the only therapeutic treatment for malignant hyperthermia (MH), a pharmacogenetic pathology affecting 0.2 over 10,000 people in the EU. It acts by inhibiting ryanodine receptors, which are responsible for calcium recruitment in striatal muscles and brain. Because of its involvement in calcium homeostasis, DAN has been successfully investigated for its potential as neuroprotecting small molecule in several animal models of Alzheimer's disease (AD). Nevertheless, its effects at a molecular level, namely on putative targets involved in neurodegeneration, are still scarcely known. Herein, we present a prospective study on repurposing of DAN involving, besides the well-known calcium antagonism, inhibition of monoamine oxidase B and acetylcholinesterase, cytoprotection from oxidative insult, and activation of carnitine/acylcarnitine carrier, as concurring biological activities responsible for neuroprotection.

PMID: 31775359 [PubMed - in process]

A comprehensive evaluation of connectivity methods for L1000 data.

Brief Bioinform. 2019 Nov 27;:

Authors: Lin K, Li L, Dai Y, Wang H, Teng S, Bao X, Lu ZJ, Wang D

Abstract
The methodologies for evaluating similarities between gene expression profiles of different perturbagens are the key to understanding mechanisms of actions (MoAs) of unknown compounds and finding new indications for existing drugs. L1000-based next-generation Connectivity Map (CMap) data is more than a thousand-fold scale-up of the CMap pilot dataset. Although several systematic evaluations have been performed individually to assess the accuracy of the methodologies for the CMap pilot study, the performance of these methodologies needs to be re-evaluated for the L1000 data. Here, using the drug-drug similarities from the Drug Repurposing Hub database as a benchmark standard, we evaluated six popular published methods for the prediction performance of drug-drug relationships based on the partial area under the receiver operating characteristic (ROC) curve at false positive rates of 0.001, 0.005 and 0.01 (AUC0.001, AUC0.005 and AUC0.01). The similarity evaluating algorithm called ZhangScore was generally superior to other methods and exhibited the highest accuracy at the gene signature sizes ranging from 10 to 200. Further, we tested these methods with an experimentally derived gene signature related to estrogen in breast cancer cells, and the results confirmed that ZhangScore was more accurate than other methods. Moreover, based on scoring results of ZhangScore for the gene signature of TOP2A knockdown, in addition to well-known TOP2A inhibitors, we identified a number of potential inhibitors and at least two of them were the subject of previous investigation. Our studies provide potential guidelines for researchers to choose the suitable connectivity method. The six connectivity methods used in this report have been implemented in R package (https://github.com/Jasonlinchina/RCSM).

PMID: 31774912 [PubMed - as supplied by publisher]

The In Silico Fischer Lock-and-Key Model: The Combined Use of Molecular Descriptors and Docking Poses for the Repurposing of Old Drugs.

Methods Mol Biol. 2020;2089:29-39

Authors: Tutone M, Almerico AM

Abstract
Not always lead compound and/or derivatives are suitable for the specific biological target for which they are designed but, in some cases, discarded compounds proved to be good binders for other biological targets; therefore, drug repurposing constitute a valid alternative to avoid waste of human and financial resources. Our virtual lock-and-key methods, VLKA and Conf-VLKA, furnish a strong support to predict the efficacy of a designed drug a priori its biological evaluation, or the correct biological target for a set of the selected compounds, allowing thus the repurposing of known and unknown, active and inactive compounds.

PMID: 31773645 [PubMed - in process]

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

J Control Release. 2018 06 28;280:113-123

Authors: Rashid J, Alobaida A, Al-Hilal TA, Hammouda S, McMurtry IF, Nozik-Grayck E, Stenmark KR, Ahsan F

Abstract
Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH.

PMID: 29723610 [PubMed - indexed for MEDLINE]

Systematically Prioritizing Candidates in Genome-Based Drug Repurposing.

Assay Drug Dev Technol. 2019 Nov 26;:

Authors: Challa AP, Lavieri RR, Lewis JT, Zaleski NM, Shirey-Rice JK, Harris PA, Aronoff DM, Pulley JM

Abstract
Drug repurposing is the application of approved drugs to treat diseases separate and distinct from their original indications. Herein, we define the scope of all practical precision drug repurposing using DrugBank, a publicly available database of pharmacological agents, and BioVU, a large, de-identified DNA repository linked to longitudinal electronic health records at Vanderbilt University Medical Center. We present a method of repurposing candidate prioritization through integration of pharmacodynamic and marketing variables from DrugBank with quality control thresholds for genomic data derived from the DNA samples within BioVU. Through the synergy of delineated "target-action pairs," along with target genomics, we identify ∼230 "pairs" that represent all practical opportunities for genomic drug repurposing. From this analysis, we present a pipeline of 14 repurposing candidates across 7 disease areas that link to our repurposability platform and present high potential for randomized controlled trial startup in upcoming months.

PMID: 31769998 [PubMed - as supplied by publisher]

Accurate repositioning of an implant interim restoration into the definitive impression to obtain an exact reproduction of tissue contours in the soft tissue cast.

J Prosthet Dent. 2019 Feb;121(2):361-362

Authors: Londono J, Blasi A, Silas J, Abreu A

PMID: 30093129 [PubMed - indexed for MEDLINE]