Mechanisms of action of metformin and its regulatory effect on microRNAs related to angiogenesis.

Pharmacol Res. 2020 Dec 19;:105390

Authors: Wang G, Lin F, Wan Q, Wu J, Luo M

Abstract
Angiogenesis is rapidly initiated in response to pathological conditions and is a key target for pharmaceutical intervention in various malignancies. Anti-angiogenic therapy has emerged as a potential and effective therapeutic strategy for treating cancer and cardiovascular-related diseases. Metformin, a first-line oral antidiabetic agent for type 2 diabetes mellitus (T2DM), not only reduces blood glucose levels and improves insulin sensitivity and exerts cardioprotective effects but also shows benefits against cancers, cardiovascular diseases, and other diverse diseases and regulates angiogenesis. MicroRNAs (miRNAs) are endogenous noncoding RNA molecules with a length of approximately 19-25 bases that are widely involved in controlling various human biological processes. A large number of miRNAs are involved in the regulation of cardiovascular cell function and angiogenesis, of which miR-21 not only regulates vascular cell proliferation, migration and apoptosis but also plays an important role in angiogenesis. The relationship between metformin and abnormal miRNA expression of has gradually been revealed in the context of numerous diseases and has received increasing attention. This paper reviews the drug-target interactions and drug repositioning events of metformin that influences vascular cells and has benefits on angiogenesis-mediated effects. Furthermore, we use miR-21 as an example to explain the specific molecular mechanism underlying metformin-mediated regulation of the miRNA signaling pathway controlling angiogenesis and vascular protective effects. These findings may provide a new therapeutic target and theoretical basis for the clinical prevention and treatment of cardiovascular diseases.

PMID: 33352227 [PubMed - as supplied by publisher]

Therapeutic Potential of Nitazoxanide: An Appropriate Choice for Repurposing versus SARS-CoV-2?

ACS Infect Dis. 2020 Dec 22;:

Authors: Stachulski AV, Taujanskas J, Pate SL, Rajoli RKR, Aljayyoussi G, Pennington SH, Ward SA, Hong WD, Biagini GA, Owen A, Nixon GL, Leung SC, O'Neill PM

Abstract
The rapidly growing COVID-19 pandemic is the most serious global health crisis since the "Spanish flu" of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for their potency and efficiency against SARS-CoV-2 in vitro and in the clinic. Here, we review the significant potential of nitazoxanide (NTZ) as an antiviral agent that can be repurposed as a treatment for COVID-19. Originally, NTZ was developed as an antiparasitic agent especially against Cryptosporidium spp.; it was later shown to possess potent activity against a broad range of both RNA and DNA viruses, including influenza A, hepatitis B and C, and coronaviruses. Recent in vitro assessment of NTZ has confirmed its promising activity against SARS-CoV-2 with an EC50 of 2.12 μM. Here we examine its drug properties, antiviral activity against different viruses, clinical trials outcomes, and mechanisms of antiviral action from the literature in order to highlight the therapeutic potential for the treatment of COVID-19. Furthermore, in preliminary PK/PD analyses using clinical data reported in the literature, comparison of simulated TIZ (active metabolite of NTZ) exposures at two doses with the in vitro potency of NTZ against SARS-CoV-2 gives further support for drug repurposing with potential in combination chemotherapy approaches. The review concludes with details of second generation thiazolides under development that could lead to improved antiviral therapies for future indications.

PMID: 33352056 [PubMed - as supplied by publisher]

Identification of fenoldopam as a novel LSD1 inhibitor to abrogate the proliferation of renal cell carcinoma using drug repurposing strategy.

Bioorg Chem. 2020 Dec 16;:104561

Authors: Zheng Y, Ma Y, Cao H, Yan L, Gu Y, Ren X, Jiao X, Wan S, Shao F

Abstract
Although targeted therapy for renal cell carcinoma (RCC) has achieved good therapeutic effects in clinic, a considerable number of patients develop drug resistance over time. So, there is still an urgent need to develop new drugs for RCC treatment. As LSD1 is considered as a promising drug target in diverse cancers, including RCC, we tried to find new LSD1 inhibitor using drug repurposing strategy from a compound library, and fenoldopam, an FDA-approved drug, was identified as a potent LSD1 inhibitor with IC50 = 0.8974 μM in a reversible manner. Molecular docking predicted that fenoldopam occupied the FAD cavity of LSD1, forming hydrogen bonds with surrounding residues. Moreover, fenoldopam inactivated LSD1 and performed antiproliferative activity against ACHN cells and promoted cells apoptosis in vitro. Taken together, fenoldopam was identified as a novel LSD1 inhibitor firstly, and may serve as a new skeleton for RCC therapy.

PMID: 33349457 [PubMed - as supplied by publisher]

Natural RNA dependent RNA polymerase inhibitors: Molecular docking studies of some biologically active alkaloids of Argemone mexicana.

Med Hypotheses. 2020 Nov;144:109905

Authors: Pandeya KB, Ganeshpurkar A, Mishra MK

Abstract
COVID-19 has become disastrous for world and spread all over. Researchers all around the globe are working to discover a drug to cure from COVID-19. RNA dependent RNA polymerase plays a key role in SARS-CoV-2 replication and thus it could be a potential target for SARS-CoV-2. This study revealed that Protopine, Allocryptopine and (±) 6- Acetonyldihydrochelerythrine could be potential RdRp inhibitors of SARS-CoV-2.

PMID: 32535456 [PubMed - indexed for MEDLINE]

From old to new - Repurposing drugs to target mitochondrial energy metabolism in cancer.

Semin Cell Dev Biol. 2020 02;98:211-223

Authors: Aminzadeh-Gohari S, Weber DD, Vidali S, Catalano L, Kofler B, Feichtinger RG

Abstract
Although we have entered the era of personalized medicine and tailored therapies, drugs that target a large variety of cancers regardless of individual patient differences would be a major advance nonetheless. This review article summarizes current concepts and therapeutic opportunities in the area of targeting aerobic mitochondrial energy metabolism in cancer. Old drugs previously used for diseases other than cancer, such as antibiotics and antidiabetics, have the potential to inhibit the growth of various tumor entities. Many drugs are reported to influence mitochondrial metabolism. However, here we consider only those drugs which predominantly inhibit oxidative phosphorylation.

PMID: 31145995 [PubMed - indexed for MEDLINE]

16 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 2020/12/22

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.

PharmKG: a dedicated knowledge graph benchmark for bomedical data mining.

Brief Bioinform. 2020 Dec 21;:

Authors: Zheng S, Rao J, Song Y, Zhang J, Xiao X, Fang EF, Yang Y, Niu Z

Abstract
Biomedical knowledge graphs (KGs), which can help with the understanding of complex biological systems and pathologies, have begun to play a critical role in medical practice and research. However, challenges remain in their embedding and use due to their complex nature and the specific demands of their construction. Existing studies often suffer from problems such as sparse and noisy datasets, insufficient modeling methods and non-uniform evaluation metrics. In this work, we established a comprehensive KG system for the biomedical field in an attempt to bridge the gap. Here, we introduced PharmKG, a multi-relational, attributed biomedical KG, composed of more than 500 000 individual interconnections between genes, drugs and diseases, with 29 relation types over a vocabulary of ~8000 disambiguated entities. Each entity in PharmKG is attached with heterogeneous, domain-specific information obtained from multi-omics data, i.e. gene expression, chemical structure and disease word embedding, while preserving the semantic and biomedical features. For baselines, we offered nine state-of-the-art KG embedding (KGE) approaches and a new biological, intuitive, graph neural network-based KGE method that uses a combination of both global network structure and heterogeneous domain features. Based on the proposed benchmark, we conducted extensive experiments to assess these KGE models using multiple evaluation metrics. Finally, we discussed our observations across various downstream biological tasks and provide insights and guidelines for how to use a KG in biomedicine. We hope that the unprecedented quality and diversity of PharmKG will lead to advances in biomedical KG construction, embedding and application.

PMID: 33341877 [PubMed - as supplied by publisher]

Ivermectin presents effective and selective antileishmanial activity in vitro and in vivo against Leishmania infantum and is therapeutic against visceral leishmaniasis.

Exp Parasitol. 2020 Dec 15;:108059

Authors: Reis TAR, Oliveira-da-Silva JA, Tavares GSV, Mendonça DVC, Freitas CS, Costa RR, Lage DP, Martins VT, Machado AS, Ramos FF, Silva AM, Ludolf F, Antinarelli LMR, Brito RCF, Chávez-Fumagalli MA, Humbert MV, Roatt BM, Coimbra ES, Coelho EAF

Abstract
Treatment for visceral leishmaniasis (VL) is hindered mainly by the toxicity and/or high cost of therapeutic drugs. In addition, parasite resistance has been registered. Thus, there is an urgent need for the identification of novel, effective and low-cost antileishmanial agents. Since drug discovery is a long and expensive process, drug repositioning for treatment of leishmaniasis should be considered. In the present study, Ivermectin (IVE), a broad-spectrum drug used for treatment of parasitic diseases, was evaluated in vitro and in vivo against Leishmania infantum species. Results in vitro showed that IVE presented 50% Leishmania and macrophage inhibitory concentrations (IC50 and CC50, respectively) of 3.64±0.48 μM and 427.50±17.60 μM, respectively, with a selectivity index (SI) of 117.45; whereas Amphotericin B (AmpB), which was used as control, showed IC50 and CC50 values of 0.12±0.05 μM and 1.06±0.23 μM, respectively, with a corresponding SI of 8.90. Treatment with IVE effectively reduced the infection percentage and parasite burden in infected and treated macrophages and displayed a prophylactic activity by inhibiting macrophage infection with pre-treated parasites. Furthermore, preliminary studies suggested that IVE targets the parasite´s mitochondria. Activity of IVE in its free format or incorporated into Pluronic® F127-based polymeric micelles (IVE/Mic) was also evaluated in vivo as a treating drug for L. infantum-infected BALB/c mice. Miltefosine was used as a control. Results showed that Miltefosine, IVE and IVE/Mic-treated animals presented significant reductions in the parasite load in their spleens, livers, bone marrows and draining lymph nodes, as well as development of an antileishmanial Th1-type immune response one and 15 days after treatment. Notably, IVE/Mic showed a better parasitological and immunological response in comparison to other alternative treatments. In conclusion, results suggest that IVE/Mic could be considered in future studies as a therapeutic alternative to treat VL.

PMID: 33338468 [PubMed - as supplied by publisher]

Tetrahydrobiopterin Improves Recognition Memory in the Triple-Transgenic Mouse Model of Alzheimer's Disease, Without Altering Amyloid-β and Tau Pathologies.

J Alzheimers Dis. 2020 Dec 15;:

Authors: Fanet H, Tournissac M, Leclerc M, Caron V, Tremblay C, Vancassel S, Calon F

Abstract
BACKGROUND: Alzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized.
OBJECTIVE: Here, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in triple-transgenic mouse model of AD (3xTg-AD) mice, a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment.
METHODS: Non-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days.
RESULTS: This sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies.
CONCLUSION: Overall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic symptoms accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.

PMID: 33337360 [PubMed - as supplied by publisher]

It Takes a Village…: Contending With Drug Shortages During Disasters.

Chest. 2020 12;158(6):2414-2424

Authors: Burry LD, Barletta JF, Williamson D, Kanji S, Maves RC, Dichter J, Christian MD, Geiling J, Erstad BL

Abstract
Critical drug shortages have been widely documented during the coronavirus disease 2019 (COVID-19) pandemic, particularly for IV sedatives used to facilitate mechanical ventilation. Surges in volume of patients requiring mechanical ventilation coupled with prolonged ventilator days and the high sedative dosing requirements observed quickly led to the depletion of "just-in-time" inventories typically maintained by institutions. This manuscript describes drug shortages in the context of global, manufacturing, regional and institutional perspectives in times of a worldwide crisis such as a pandemic. We describe etiologic factors that lead to drug shortages including issues related to supply (eg, manufacturing difficulties, supply chain breakdowns) and variables that influence demand (eg, volatile prescribing practices, anecdotal or low-level data, hoarding). In addition, we describe methods to mitigate drug shortages as well as conservation strategies for sedatives, analgesics and neuromuscular blockers that could readily be applied at the bedside. The COVID-19 pandemic has accentuated the need for a coordinated, multi-pronged approach to optimize medication availability as individual or unilateral efforts are unlikely to be successful.

PMID: 32805237 [PubMed - indexed for MEDLINE]

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 2020/12/18

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 2020/12/17

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 2020/12/16

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 2020/12/16

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.

53 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 2020/12/15

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.

50 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 2020/12/15

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.

Comput Struct Biotechnol J. 2020;18:3947-3949. doi: 10.1016/j.csbj.2020.11.054. Epub 2020 Dec 6.

ABSTRACT

Adaptive clinical trials are underway to determine the efficacy of potential therapies for COVID-19, with flexibility to include emerging therapies if there is sufficient preclinical evidence for their potential utility. In silico screening of connectivity maps, which link gene expression profiles to libraries of perturbagens, may facilitate the identification of such emerging therapies. The L1000 Connectivity Map is built from samples of transcripts taken from gene expression profiles of cells in various experimental conditions followed by computational inferences of the remainder of the transcriptome. Searching the L1000 Connectivity Map for modulators of a protease that facilitates coronavirus infection identifies plausible candidate drugs for repurposing as antiviral agents against SARS-CoV-2 following further investigation.

PMID:33312454 | PMC:PMC7719280 | DOI:10.1016/j.csbj.2020.11.054

Targeting abnormal metabolism in Alzheimer's disease: The Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study.

Alzheimers Dement (N Y). 2020;6(1):e12095

Authors: Desai RJ, Varma VR, Gerhard T, Segal J, Mahesri M, Chin K, Nonnenmacher E, Gabbeta A, Mammen AM, Varma S, Horton DB, Kim SC, Schneeweiss S, Thambisetty M

Abstract
Drug discovery for disease-modifying therapies for Alzheimer's disease and related dementias (ADRD) based on the traditional paradigm of experimental animal models has been disappointing. We describe the rationale and design of the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study, an innovative multidisciplinary alternative to traditional drug discovery. First, we use a systems biology perspective in the "hypothesis generation" phase to identify metabolic abnormalities that may either precede or interact with the accumulation of ADRD neuropathology, accelerating the expression of clinical symptoms of the disease. Second, in the "hypothesis refinement" phase we propose use of large patient cohorts to test whether drugs approved for other indications that also target metabolic drivers of ADRD pathogenesis might alter the trajectory of the disease. We emphasize key challenges in population-based pharmacoepidemiologic studies aimed at quantifying the association between medication use and ADRD onset and outline robust causal inference principles to safeguard against common pitfalls. Candidate ADRD treatments emerging from this approach will hold promise as plausible disease-modifying therapies for evaluation in randomized controlled trials.

PMID: 33304987 [PubMed]

Repurposing Known Drugs as Covalent and Non-covalent Inhibitors of the SARS-CoV-2 Papain-Like Protease.

Front Chem. 2020;8:594009

Authors: Delre P, Caporuscio F, Saviano M, Mangiatordi GF

Abstract
In the absence of an approved vaccine, developing effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antivirals is essential to tackle the current pandemic health crisis due to the coronavirus disease 2019 (COVID-19) spread. As any traditional drug discovery program is a time-consuming and costly process requiring more than one decade to be completed, in silico repurposing of existing drugs is the preferred way for rapidly selecting promising clinical candidates. We present a virtual screening campaign to identify covalent and non-covalent inhibitors of the SARS-CoV-2 papain-like protease (PLpro) showing potential multitarget activities (i.e., a desirable polypharmacology profile) for the COVID-19 treatment. A dataset including 688 phase III and 1,702 phase IV clinical trial drugs was downloaded from ChEMBL (version 27.1) and docked to the recently released crystal structure of PLpro in complex with a covalently bound peptide inhibitor. The obtained results were analyzed by combining protein-ligand interaction fingerprint similarities, conventional docking scores, and MM-GBSA-binding free energies and allowed the identification of some interesting candidates for further in vitro testing. To the best of our knowledge, this study represents the first attempt to repurpose drugs for a covalent inhibition of PLpro and could pave the way for new therapeutic strategies against COVID-19.

PMID: 33304884 [PubMed]

Silybin B and Cianidanol Inhibit M pro and Spike Protein of SARS-CoV-2: Evidence from in Silico Molecular Docking Studies.

Curr Pharm Des. 2020 Dec 10;:

Authors: Srivastava R, Tripathi S, Unni S, Hussain A, Haque S, Dasgupta N, Singh V, Mishra BN

Abstract
BACKGROUND: The main proteases (Mpro) and Spike Proteins (SP) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV-2) play a major role in viral infection development by producing several non-structural proteins (nsPs) and penetrating the host cells respectively. In this study, the potential of in silico molecular docking-based drug repositioning approach was exploited for identifying the inhibitors of Mpro and SP of SARS-CoV-2.
METHODS: A total of 196 compounds including various US-FDA-approved drugs, vitamins and their analogs were docked with Mpro (PDB IDs: 6YB7 and 6Y84), and the top six ligands were further tested for ADME properties followed by docking with SP (PDB IDs: 6LXT and 6W41).
RESULTS: Out of 196 compounds, binding energy (DE) of Silybin B (6YB7: DE: -11.20 kcal/mol; 6Y84: DE: -10.18 kcal/mol; 6LXT:DE: -10.47 kcal/mol; 6W41:DE: -10.96 kcal/mol) and Cianidanol (6YB7:DE: -8.85 kcal/mol; 6Y84:DE:-10.02 kcal/mol; 6LXT:DE:-9.36 kcal/mol; 6W41:DE: -9.52 kcal/mol) demonstrated better binding and ADME properties compared with the currently endeavored drugs like Hydroxychloroquine and Lopinavir. Additionally, Elliptinone, Diospyirin, SCHEMBL94263 and Fiboflavin have shown encouraging results. Fiboflavin, an immunity booster, was found to inhibit both the Mpro and spike protein of SARS-CoV-2. It was observed that amino acid residues MET6, ALA7, PHE8, PRO9, ASP295, GLY302, VAL303 and THR304 play significant roles in protein-ligand interactions through hydrogen bonds and Vander Waals forces.
CONCLUSION: Silybin B and Cianidanol showed excellent binding and ADME properties compared with the currently endeavored drugs and can be exploited as therapeutic options against SARS-CoV-2 infection after experimental validation and clinical trials.

PMID: 33302853 [PubMed - as supplied by publisher]