Nonglycemic Effects of GLP-1 Agonists: From a Starling to Lizards to People.

Metab Syndr Relat Disord. 2019 Jul/Aug;17(6):303-313

Authors: Sood A, Swislocki A

Abstract
With the approval of exenatide in 2005, physicians had a new class of hypoglycemic agents available for the treatment of type 2 diabetes-the glucagon-like peptide-1 receptor agonists (or GLP-1 receptor agonists). As of this writing, there are seven drugs in this class available in the United States. In addition to demonstrating either cardiovascular risk neutrality or overt benefit, as now mandated by the United States Food and Drug Administration (FDA), many of these drugs have other, unexpected actions. It is our goal to outline these actions, some beneficial, some not. We have reviewed English-language articles in this area, not for an exhaustive study, but rather a broad search to define current understanding and perhaps generate further investigation.

PMID: 31145029 [PubMed - indexed for MEDLINE]

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/29

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/28

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

6 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/27

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Computational Models and Methods for Drug Target Prediction and Drug Repositioning.

Comb Chem High Throughput Screen. 2020;23(4):270-273

Authors: Huang G

PMID: 32452755 [PubMed - as supplied by publisher]

An up-to-date overview of computational polypharmacology in modern drug discovery.

Expert Opin Drug Discov. 2020 May 26;:1-20

Authors: Chaudhari R, Fong LW, Tan Z, Huang B, Zhang S

Abstract
INTRODUCTION: In recent years, computational polypharmacology has gained significant attention to study the promiscuous nature of drugs. Despite tremendous challenges, community-wide efforts have led to a variety of novel approaches for predicting drug polypharmacology. In particular, some rapid advances using machine learning and artificial intelligence have been reported with great success.
AREAS COVERED: In this article, the authors provide a comprehensive update on the current state-of-the-art polypharmacology approaches and their applications, focusing on those reports published after our 2017 review article. The authors particularly discuss some novel, groundbreaking concepts, and methods that have been developed recently and applied to drug polypharmacology studies.
EXPERT OPINION: Polypharmacology is evolving and novel concepts are being introduced to counter the current challenges in the field. However, major hurdles remain including incompleteness of high-quality experimental data, lack of in vitro and in vivo assays to characterize multi-targeting agents, shortage of robust computational methods, and challenges to identify the best target combinations and design effective multi-targeting agents. Fortunately, numerous national/international efforts including multi-omics and artificial intelligence initiatives as well as most recent collaborations on addressing the COVID-19 pandemic have shown significant promise to propel the field of polypharmacology forward.

PMID: 32452701 [PubMed - as supplied by publisher]

Repurposing Quaternary Ammonium Compounds as Potential Treatments for COVID-19.

Pharm Res. 2020 May 25;37(6):104

Authors: Baker N, Williams AJ, Tropsha A, Ekins S

Abstract
The COVID-19 pandemic has highlighted an important role for drug repurposing. Quaternary ammonium compounds such as ammonium chloride, cetylpyridinium and miramistin represent widely accessible antiseptic molecules with well-known broad-spectrum antiviral activities and represent a repurposing opportunity as therapeutics against SARS-CoV-2.

PMID: 32451736 [PubMed - in process]

Chloroquine and hydroxychloroquine repositioning in times of COVID-19 pandemics, all that glitters is not gold.

Cad Saude Publica. 2020;36(5):e00088520

Authors: Paumgartten FJR, Delgado IF, Pitta LDR, Oliveira ACAX

PMID: 32428074 [PubMed - indexed for MEDLINE]

The influence of ketamine on drug discovery in depression.

Drug Discov Today. 2019 10;24(10):2033-2043

Authors: Kraus C, Wasserman D, Henter ID, Acevedo-Diaz E, Kadriu B, Zarate CA

Abstract
Recent research demonstrating that the glutamatergic modulator ketamine has rapid, robust, and sustained antidepressant effects has been a turning point in drug discovery for depression. The recent FDA approval of esketamine for adults with treatment-resistant major depressive disorder (MDD) has further underscored the relevance of this agent in spurring investigation into novel and mechanistically distinct agents for use in depression. Over the past two decades, ketamine research has ushered in a new wave of studies seeking to not only identify its mechanism of action but also to examine the antidepressant potential of novel or repurposed agents. This article reviews the approaches that have proven particularly fruitful for the field of neuropsychiatry.

PMID: 31382015 [PubMed - indexed for MEDLINE]

N-p-Tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibits HIV-1 by suppressing the activity of viral protease.

Biochem Biophys Res Commun. 2020 Jun 18;527(1):167-172

Authors: Trivedi J, Ghosh P, Mitra D

Abstract
Human Immunodeficiency Virus (HIV), the etiological agent for Acquired Immunodeficiency Syndrome (AIDS), continues to kill humans despite stupendous advances in antiviral research. With the presently available combination antiretroviral therapeutic arsenal, AIDS is now a manageable disease but with no cure available till date. The development of novel antivirals consumes an extensive amount of time and resources. Hence, repurposing of the established gold standard molecules for their anti-HIV application is enormously advantageous. In this study, we report that N-p-Tosyl-L-phenylalanine chloromethyl ketone (TPCK) inhibits HIV-1 replication in a highly-conserved manner. Further, TPCK inhibits HIV-1 replication at the late stages of its life cycle by impeding viral protease (PR) enzyme activity. Additionally, our results demonstrate that the combination of TPCK with established HIV-1 PR inhibitors shows significant synergistic inhibitory potential, suggesting the potential use of TPCK in cART regimen. Collectively, we report the anti-HIV activity of TPCK, which should be further characterized for its translational applications.

PMID: 32446362 [PubMed - as supplied by publisher]

The Landscape of Human Cancer Proteins Targeted by SARS-CoV-2.

Cancer Discov. 2020 May 22;:

Authors: Tutuncuoglu B, Cakir M, Batra J, Bouhaddou M, Eckhardt M, Gordon DE, Krogan NJ

Abstract
Mapping SARS-CoV-2-human protein-protein interactions by Gordon et al. revealed druggable targets that are hijacked by the virus. Here, we highlight several oncogenic pathways identified at the host-virus interface of SARS-CoV-2 to enable cancer biologists apply their knowledge for rapid drug repurposing to treat COVID-19, and help inform the response to potential long-term complications of the disease.

PMID: 32444466 [PubMed - as supplied by publisher]

A Selective Serotonin Reuptake Inhibitor, a Proton Pump Inhibitor, and Two Calcium Channel Blockers Inhibit Candida albicans Biofilms.

Microorganisms. 2020 May 18;8(5):

Authors: Nobile CJ, Ennis CL, Hartooni N, Johnson AD, Lohse MB

Abstract
Biofilms formed by the human fungal pathogen Candida albicans are naturally resistant to many of the antifungal agents commonly used in the clinic. We screened a library containing 1600 clinically tested drug compounds to identify compounds that inhibit C. albicans biofilm formation. The compounds that emerged from the initial screen were validated in a secondary screen and then tested for (1) their abilities to disrupt mature biofilms and (2) for synergistic interactions with representatives of the three antifungal agents most commonly prescribed to treat Candida infections, fluconazole, amphotericin B, and caspofungin. Twenty compounds had antibiofilm activity in at least one of the secondary assays and several affected biofilms but, at the same concentration, had little or no effect on planktonic (suspension) growth of C. albicans. Two calcium channel blockers, a selective serotonin reuptake inhibitor, and an azole-based proton pump inhibitor were among the hits, suggesting that members of these three classes of drugs or their derivatives may be useful for treating C. albicans biofilm infections.

PMID: 32443498 [PubMed - as supplied by publisher]

Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: Possible therapeutic implication in COVID-19.

Biosci Rep. 2020 May 22;:

Authors: Shamsi A, Mohammad T, Anwar S, Alajmi M, Hussain A, Rehman MT, Islam A, Hassan MI

Abstract
Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of SARS-CoV-2. Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential protein, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc as the best inhibitors CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and Maraviroc bind to the conserved substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and Maraviroc for the therapeutic management of COVID-19.

PMID: 32441299 [PubMed - as supplied by publisher]

Repurposing Disulfiram as an Anti-Obesity Drug: Treating and Preventing Obesity in High-Fat-Fed Rats.

Diabetes Metab Syndr Obes. 2020;13:1473-1480

Authors: Omran Z, Sheikh R, Baothman OA, Zamzami MA, Alarjah M

Abstract
Background and Objectives: A drug repurposing strategy is an approach for identifying new therapeutic uses for approved or investigational drugs. Thanks to the moderate cost of repurposing a drug compared to bringing new chemical entity to the market, drug repurposing is rapidly gaining ground. The aim of this work is to study the anti-obesity effect of disulfiram (DSF), an irreversible aldehyde dehydrogenase inhibitor approved by the Food and Drug Administration (FDA) to treat chronic alcoholism since 1951.
Methods: Thirty male Albino rats were randomly assigned to six groups. G1, the control group, was given a standard diet. G2, the positive control group, was given a high-fat diet (HFD). G3 was given an HFD, and DSF 50 mg/kg/day was administered orally from day one for six weeks. G4 was given an HFD, and DSF 200 mg/kg/day was administered orally from day one for six weeks. G5 was given an HFD for six weeks; then treatment started with 50 mg/kg/day DSF orally. G6 was given an HFD for six weeks; then treatment started with 200 mg/kg/day DSF orally for three weeks. The body weight, food consumption and blood glucose levels were monitored over the given time interval.
Results: Both doses of DSF significantly limited the body weight gain caused by an HFD for the treated animals. HF-fed rats received 50 and 200 mg/kg/day of DSF had their body weight increased by 51.93 ± 7.89% and 20.88 ± 15.05% respectively, whereas the body weight of control animals increased by 93.1 ± 20.04%. DSF also significantly decreased the body weight of obese animals. At 50 and 200 mg/kg/day of DSF, HF-fed rats lost 16.74 ± 8.61% and 23.9 ± 3.93% respectively, as their untreated counterparts had their body weight increased by 11.85 ± 3.79% after three weeks of treatment, thus restoring a body weight matching those who received a standard diet.
Conclusion: FDA-approved disulfiram has a strong anti-obesity effect on HFD-fed rats.

PMID: 32440176 [PubMed]

Robust Sampling of Defective Pathways in Alzheimer's Disease. Implications in Drug Repositioning.

Int J Mol Sci. 2020 May 19;21(10):

Authors: Fernández-Martínez JL, Álvarez-Machancoses Ó, de Andrés-Galiana EJ, Bea G, Kloczkowski A

Abstract
We present the analysis of the defective genetic pathways of the Late-Onset Alzheimer's Disease (LOAD) compared to the Mild Cognitive Impairment (MCI) and Healthy Controls (HC) using different sampling methodologies. These algorithms sample the uncertainty space that is intrinsic to any kind of highly underdetermined phenotype prediction problem, by looking for the minimum-scale signatures (header genes) corresponding to different random holdouts. The biological pathways can be identified performing posterior analysis of these signatures established via cross-validation holdouts and plugging the set of most frequently sampled genes into different ontological platforms. That way, the effect of helper genes, whose presence might be due to the high degree of under determinacy of these experiments and data noise, is reduced. Our results suggest that common pathways for Alzheimer's disease and MCI are mainly related to viral mRNA translation, influenza viral RNA transcription and replication, gene expression, mitochondrial translation, and metabolism, with these results being highly consistent regardless of the comparative methods. The cross-validated predictive accuracies achieved for the LOAD and MCI discriminations were 84% and 81.5%, respectively. The difference between LOAD and MCI could not be clearly established (74% accuracy). The most discriminatory genes of the LOAD-MCI discrimination are associated with proteasome mediated degradation and G-protein signaling. Based on these findings we have also performed drug repositioning using Dr. Insight package, proposing the following different typologies of drugs: isoquinoline alkaloids, antitumor antibiotics, phosphoinositide 3-kinase PI3K, autophagy inhibitors, antagonists of the muscarinic acetylcholine receptor and histone deacetylase inhibitors. We believe that the potential clinical relevance of these findings should be further investigated and confirmed with other independent studies.

PMID: 32438758 [PubMed - in process]

8 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

7 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"drug repositioning" OR "drug repurposing"

These pubmed results were generated on 2020/05/22

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Known Antimicrobials Versus Nortriptyline in Candida albicans: Repositioning an Old Drug for New Targets.

Microorganisms. 2020 May 15;8(5):

Authors: Caldara M, Marmiroli N

Abstract
Candida albicans has the capacity to develop resistance to commonly used antimicrobials, and to solve this problem, drug repositioning and new drug combinations are being studied. Nortriptyline, a tricyclic antidepressant, was shown to have the capacity to inhibit biofilm and hyphae formation, along with the ability to efficiently kill cells in a mature biofilm. To use nortriptyline as a new antimicrobial, or in combination with known drugs to increase their actions, it is important to characterize in more detail the effects of this drug on the target species. In this study, the Candida albicans GRACE ™ collection and a Haplo insufficiency profiling were employed to identify the potential targets of nortriptyline, and to classify, in a parallel screening with amphotericin B, caspofungin, and fluconazole, general multi-drug resistance genes. The results identified mutants that, during biofilm formation and upon treatment of a mature biofilm, are sensitive or tolerant to nortriptyline, or to general drug treatments. Gene ontology analysis recognized the categories of ribosome biogenesis and spliceosome as enriched upon treatment with the tricyclic antidepressant, while mutants in oxidative stress response and general stress response were commonly retrieved upon treatment with any other drug. The data presented suggest that nortriptyline can be considered a "new" antimicrobial drug with large potential for application to in vivo infection models.

PMID: 32429222 [PubMed]