Repurposing Drugs for COVID-19: An Approach for Treatment in the Pandemic.

Altern Ther Health Med. 2020 Aug 20;:

Authors: Khadka S, Yuchi A, Shrestha DB, Budhathoki P, Al-Subari SMM, Ziad Alhouzani TM, Anwar Butt I

Abstract
Context: Drug repurposing is a relevant approach during the COVID-19 pandemic, because development of new drugs is time-consuming and costly, and the safety of new drugs is paramount. Drug repurposing focuses on researching new indications for existing drugs and can reduce the challenges faced in drug development.
Objective: The current review intended to examine the current status of drugs being repurposed for COVID-19 treatment.
Design: The research team performed a literature review, searching relevant literature databases to find abstracts of relevant articles in journals published from 2010 until May 16, 2020. The sources of data included Google Scholar, PubMed, and ScienceDirect. The search terms used included repositioning of drugs, repurposing of drugs and COVID-19 therapy, and SARS-CoV-2 therapy.
Setting: The research team conducted this study at the Department of Pharmacology, Punjab University College of Pharmacy, University of the Punjab, Lahore, Pakistan; Mangalbare Hospital, Morang, Nepal; and Dr Iwamura Memorial Hospital, Bhaktapur, Nepal.
Results: Repurposing of drugs from different pharmacological groups including antivirals like remdesivir, lopinavir, ritonavir, arbidol, oseltamivir, penciclovir, favipiravir, ganciclovir, and ribavirin; other antibiotics like azithromycin, ivermectin, eravacycline, valrubicin, streptomycin, nitazoxanide, teicoplanin, caspofungin, and colistin; and other agents like hydroxychloroquine, chloroquine, tocilizumab, camostat, nafamostat, carfilzomib, interferon, aprepitant, and dexamethasone can be considered for COVID-19 therapy.
Conclusions: Although current results are promising, limitations to drug repurposing, such as a low success rate and the possibility of adverse events, can't be overlooked. With continuous research and technical advancements, repurposing will no doubt provide a notable scientific contribution to innovation in drug development and pharmacotherapy practice for the treatment of new diseases or existing diseases in a new way.

PMID: 32827400 [PubMed - as supplied by publisher]

Multiple drug-induced stress responses inhibit formation of Escherichia coli biofilms.

Appl Environ Microbiol. 2020 Aug 21;:

Authors: Teteneva NA, Mart'yanov SV, Esteban López M, Kahnt J, Glatter T, Netrusov AI, Plakunov VK, Sourjik V

Abstract
In most ecosystems, bacteria primarily exist as structured surface-associated biofilms that can be highly tolerant to antibiotics and thus represent an important health issue. Here we explored drug repurposing as a strategy to identify new antibiofilm compounds, screening over 1000 compounds from the Prestwick Chemical Library of approved drugs for specific activities that prevent biofilm formation by Escherichia coli Most growth-inhibiting compounds, which include known antibacterial but also antiviral and other drugs, had also reduced biofilm formation. However, we also identified several drugs that were biofilm-inhibitory at doses where only weak or no effect on planktonic growth could be observed. Activities of the most specific antibiofilm compounds were further characterized using gene expression analysis, proteomics and microscopy. We observed that most of these drugs acted by repressing genes responsible for production of curli, major component of E. coli biofilm matrix. This repression apparently occurred through induction of several different stress responses, including DNA and cell-wall damage, and homeostasis of divalent cations, demonstrating that biofilm formation can be inhibited through a variety of molecular mechanisms. One tested drug, tyloxapol, inhibited biofilm formation independent of curli expression or growth, by suppressing bacterial attachment at the surface.Importance Prevention of bacterial biofilm formation is one of the major current challenges in microbiology. By systematically screening a large number of approved drugs for their ability to suppress biofilm formation by Escherichia coli, here we identified a number of prospective antibiofilm compounds. We further demonstrated different mechanisms of action for individual compounds, from induction of replicative stress to disbalance of cation homeostasis to inhibition of bacterial attachment to the surface. Our work demonstrates the potential of drug repurposing for the prevention of bacterial biofilm formation and suggests that also for other bacteria the activity spectrum of antibiofilm compounds is likely to be broad.

PMID: 32826218 [PubMed - as supplied by publisher]

Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Viperinae Snake Venom Toxins.

Biomedicines. 2020 Aug 20;8(9):

Authors: Xie C, Albulescu LO, Bittenbinder MA, Somsen GW, Vonk FJ, Casewell NR, Kool J

Abstract
Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A2 (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in Viperinae snake venoms. The venoms of Echis carinatus, Echis ocellatus, Daboia russelii and Bitis arietans, which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A2-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming.

PMID: 32825484 [PubMed - as supplied by publisher]

Repositioning Dequalinium as Potent Muscarinic Allosteric Ligand by Combining Virtual Screening Campaigns and Experimental Binding Assays.

Int J Mol Sci. 2020 Aug 19;21(17):

Authors: Mazzolari A, Gervasoni S, Pedretti A, Fumagalli L, Matucci R, Vistoli G

Abstract
Structure-based virtual screening is a truly productive repurposing approach provided that reliable target structures are available. Recent progresses in the structural resolution of the G-Protein Coupled Receptors (GPCRs) render these targets amenable for structure-based repurposing studies. Hence, the present study describes structure-based virtual screening campaigns with a view to repurposing known drugs as potential allosteric (and/or orthosteric) ligands for the hM2 muscarinic subtype which was indeed resolved in complex with an allosteric modulator thus allowing a precise identification of this binding cavity. First, a docking protocol was developed and optimized based on binding space concept and enrichment factor optimization algorithm (EFO) consensus approach by using a purposely collected database including known allosteric modulators. The so-developed consensus models were then utilized to virtually screen the DrugBank database. Based on the computational results, six promising molecules were selected and experimentally tested and four of them revealed interesting affinity data; in particular, dequalinium showed a very impressive allosteric modulation for hM2. Based on these results, a second campaign was focused on bis-cationic derivatives and allowed the identification of other two relevant hM2 ligands. Overall, the study enhances the understanding of the factors governing the hM2 allosteric modulation emphasizing the key role of ligand flexibility as well as of arrangement and delocalization of the positively charged moieties.

PMID: 32825082 [PubMed - as supplied by publisher]

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 2020/08/22

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.

Utilizing drug repurposing against COVID-19 - Efficacy, limitations, and challenges.

Life Sci. 2020 Aug 17;:118275

Authors: Parvathaneni V, Gupta V

Abstract
The recent outbreak of Coronavirus disease (COVID-19), first in Eastern Asia and then essentially across the world has been declared a pandemic by the WHO. COVID-19 is caused by a novel virus SARS-CoV2 (2019-nCoV), against which there is currently no vaccine available; and current antiviral therapies have failed, causing a very high mortality rate. Drug repurposing i.e. utilizing an approved drug for different indication, offers a time- and cost-efficient alternative for making new therapies available to patients. Although there are several reports presenting novel approaches to treat COVID-19, still an attentive review of previous scientific literature is essential to overcome their failure to exhibit efficacy. There is an urgent need to provide a comprehensive outlook toward utilizing drug repurposing as a tool for discovery of new therapies against COVID-19. In this article, we aim to provide a to-the-point review of current literature regarding efficacy of repurposed drugs against COVID-19 and other respiratory infections caused by coronaviruses. We have briefly discussed COVID-19 epidemiology, and then have discussed drug repurposing approaches and examples, specific to respiratory viruses. Limitations of utilization of repurposed drug molecules such as dosage regimen and associated challenges such as localized delivery in respiratory tract have also been discussed in detail.

PMID: 32818545 [PubMed - as supplied by publisher]

DREIMT: a drug repositioning database and prioritization tool for immunomodulation.

Bioinformatics. 2020 Aug 20;:

Authors: Troulé K, López-Fernández H, García-Martín S, Reboiro-Jato M, Carretero-Puche C, Martorell-Marugán J, Martín-Serrano G, Carmona-Sáez P, González-Peña D, Al-Shahrour F, Gómez-López G

Abstract
MOTIVATION: Drug immunomodulation modifies the response of the immune system and can be therapeutically exploited in pathologies such as cancer and autoimmune diseases.
RESULTS: DREIMT is a new hypothesis-generation web tool which performs drug prioritization analysis for immunomodulation. DREIMT provides significant immunomodulatory drugs targeting up to 70 immune cells subtypes through a curated database that integrates 4,960 drug profiles and ∼2,6K immune gene expression signatures. The tool also suggests potential immunomodulatory drugs targeting user-supplied gene expression signatures. Final output includes drug-signature association scores, FDRs and downloadable plots and results tables.
AVAILABILITY: http://www.dreimt.org.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 32818254 [PubMed - as supplied by publisher]

Molecular docking and simulation studies on SARS-CoV-2 Mpro reveals Mitoxantrone, Leucovorin, Birinapant, and Dynasore as potent drugs against COVID-19.

J Biomol Struct Dyn. 2020 Aug 20;:1-12

Authors: Lokhande KB, Doiphode S, Vyas R, Swamy KV

Abstract
The outbreak of novel coronavirus (COVID-19), which began from Wuhan City, Hubei, China, and declared as a Public Health Emergency of International Concern by World Health Organization (WHO) on 30th January 2020. The present study describes how the available drug candidates can be used as a potential SARS-CoV-2 Mpro inhibitor by molecular docking and molecular dynamic simulation studies. Drug repurposing strategy is applied by using the library of antiviral and FDA approved drugs retrieved from the Selleckchem Inc. (Houston, TX, http://www.selleckchem.com) and DrugBank database respectively. Computational methods like molecular docking and molecular dynamics simulation were used. The molecular docking calculations were performed using LeadIT FlexX software. The molecular dynamics simulations of 100 ns were performed to study conformational stability for all complex systems. Mitoxantrone and Leucovorin from FDA approved drug library and Birinapant and Dynasore from anti-viral drug libraries interact with SARS-CoV-2 Mpro at higher efficiency as a result of the improved steric and hydrophobic environment in the binding cavity to make stable complex. Also, the molecular dynamics simulations of 100 ns revealed the mean RMSD value of 2.25 Å for all the complex systems. This shows that lead compounds bound tightly within the Mpro cavity and thus having conformational stability. Glutamic acid (Glu166) of Mpro is a key residue to hold and form a stable complex of reported lead compounds by forming hydrogen bonds and salt bridge. Our findings suggest that Mitoxantrone, Leucovorin, Birinapant, and Dynasore represents potential inhibitors of SARS-CoV-2 Mpro.

PMID: 32815481 [PubMed - as supplied by publisher]

Mouse Model for Efficient Simultaneous Targeting of Glycolysis, Glutaminolysis, and De Novo Synthesis of Fatty Acids in Colon Cancer.

Methods Mol Biol. 2021;2174:45-69

Authors: Schcolnik-Cabrera A, Dueñas-Gonzalez A

Abstract
Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.

PMID: 32813244 [PubMed - as supplied by publisher]

Computational repositioning of dimethyl fumarate for treating alcoholic liver disease.

Cell Death Dis. 2020 Aug 18;11(8):641

Authors: Zhang Y, Zhao S, Fu Y, Yan L, Feng Y, Chen Y, Wu Y, Deng Y, Zhang G, Chen Z, Chen Y, Liu T

Abstract
Alcoholic liver disease (ALD) is a chronic alcohol-induced disorder of the liver for which there are few effective therapies for severe forms of ALD and for those who do not achieve alcohol abstinence. In this study, we used a systematic drug-repositioning bioinformatics approach querying a large compendium of gene-expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat ALD. One of the top compounds predicted to be therapeutic for ALD by our approach was dimethyl fumarate (DMF), an nuclear factor erythroid 2-related factor 2 (NRF2) inducer. We experimentally validated DMF in liver cells and in vivo. Our work demonstrates that DMF is able to significantly upregulate the NRF2 protein level, increase NRF2 phosphorylation, and promote NRF2 nuclear localization in liver cells. DMF also reduced the reactive oxygen species (ROS) level, lipid peroxidation, and ferroptosis. Furthermore, DMF treatment could prevent ethanol-induced liver injury in ALD mice. Our results provide evidence that DMF might serve as a therapeutic option for ALD in humans, and support the use of computational repositioning to discover therapeutic options for ALD.

PMID: 32811823 [PubMed - in process]

Drug repositioning in cancer: a role for antihistamines in breast cancer?

Acta Oncol. 2020 Aug 19;:1-2

Authors: Nilbert M, Mellemkjær L

PMID: 32811253 [PubMed - as supplied by publisher]

Activation of KCNQ Channels Prevents Paclitaxel-Induced Peripheral Neuropathy and Associated Neuropathic Pain.

J Pain. 2019 05;20(5):528-539

Authors: Li L, Li J, Zuo Y, Dang D, Frost JA, Yang Q

Abstract
Paclitaxel-induced peripheral neuropathy (PIPN) and associated neuropathic pain are the most common and serious adverse effects experienced by cancer patients receiving paclitaxel treatment. These effects adversely impact daily activities and consequently the quality of life, sometimes forcing the suspension of treatment and negatively influencing survival. Patients are usually at high risk of developing PIPN if paclitaxel induces acute pain, which strongly suggests that an acute increase in the excitability of nociceptors underlies the chronic alterations of PIPN. KCNQ/Kv7 channels are widely expressed in the primary sensory neurons to modulate their excitability. In the present study, we show that targeting KCNQ/Kv7 channels at an early stage is an effective strategy to attenuate the development of PIPN. We found that paclitaxel did not decrease the expression level of KCNQ/Kv7 channels in the primary sensory neurons as detected by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting. However, retigabine, which is a specific KCNQ/Kv7 channel opener, attenuated significantly the development of PIPN, as shown by both morphologic and behavioral evidence. We also observed that retigabine had no obvious effect on the chemosensitivity of breast cancer cells to paclitaxel. Although retigabine has been approved by the FDA as an anticonvulsant, our study suggests that this drug can be repurposed to attenuate the development of PIPN. PERSPECTIVE: Paclitaxel-induced peripheral neuropathy and associated neuropathic pain are severe and resistant to intervention. The results of our study demonstrated that retigabine (a clinically available medicine) can be used to attenuate the development of paclitaxel-induced peripheral neuropathy.

PMID: 30471428 [PubMed - indexed for MEDLINE]

An integrated drug repurposing strategy for the rapid identification of potential SARS-CoV-2 viral inhibitors.

Sci Rep. 2020 Aug 17;10(1):13866

Authors: Trezza A, Iovinelli D, Santucci A, Prischi F, Spiga O

Abstract
The Coronavirus disease 2019 (COVID-19) is an infectious disease caused by the severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). The virus has rapidly spread in humans, causing the ongoing Coronavirus pandemic. Recent studies have shown that, similarly to SARS-CoV, SARS-CoV-2 utilises the Spike glycoprotein on the envelope to recognise and bind the human receptor ACE2. This event initiates the fusion of viral and host cell membranes and then the viral entry into the host cell. Despite several ongoing clinical studies, there are currently no approved vaccines or drugs that specifically target SARS-CoV-2. Until an effective vaccine is available, repurposing FDA approved drugs could significantly shorten the time and reduce the cost compared to de novo drug discovery. In this study we attempted to overcome the limitation of in silico virtual screening by applying a robust in silico drug repurposing strategy. We combined and integrated docking simulations, with molecular dynamics (MD), Supervised MD (SuMD) and Steered MD (SMD) simulations to identify a Spike protein - ACE2 interaction inhibitor. Our data showed that Simeprevir and Lumacaftor bind the receptor-binding domain of the Spike protein with high affinity and prevent ACE2 interaction.

PMID: 32807895 [PubMed - in process]

Repurposed agents in the Alzheimer's disease drug development pipeline.

Alzheimers Res Ther. 2020 Aug 17;12(1):98

Authors: Bauzon J, Lee G, Cummings J

Abstract
BACKGROUND: Treatments are needed to address the growing prevalence of Alzheimer's disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes.
METHODS: We assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020.
RESULTS: We identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov.
CONCLUSIONS: Drug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

PMID: 32807237 [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 2020/08/18

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.

Teaching the basics of repurposing mitochondria-targeted drugs: From Parkinson's disease to cancer and back to Parkinson's disease.

Redox Biol. 2020 Aug 03;36:101665

Authors: Kalyanaraman B

Abstract
Parkinson's disease (PD) and cancer share common mutations in mitochondrial proteins: Parkin and PINK1. The overlapping of genes involved in PD and cancer implies that the two diseases might share a common pathogenic mechanism. There are other compelling rationales for a mechanistic link between these diseases. Mitochondria and autophagy/mitophagy are emerging as therapeutic targets in PD and cancer: Ongoing research in our laboratories has shown that, when administered early, mitochondria-targeted agents afford neuroprotection in preclinical mice models of PD. Also, we discovered that mitochondria-targeted drugs inhibit tumor cell proliferation. We propose that mitochondrial targeting stimulates conservation of cellular energy critical for neuronal cell survival, whereas the energy conservation mechanism inhibits proliferation of cancer cells by depriving the energy necessary for cancer cell growth. We propose a promising drug repurposing strategy involving mitochondria-targeted drugs synthesized from naturally occurring molecules and FDA-approved drugs that are relatively nontoxic in both PD and cancer. These compounds have been shown to induce various cellular signaling pathways for autophagy/mitophagy, anti-inflammatory, and immunomodulatory effects that are implicated as therapeutic mechanisms in PD and cancer.

PMID: 32795938 [PubMed - as supplied by publisher]

Computational-based drug repurposing methods in COVID-19.

Bioimpacts. 2020;10(3):205-206

Authors: Masoudi-Sobhanzadeh Y

Abstract
COVID-19, as a newly emerging disease, has disrupted human's different activities. Hence, it is essential to develop drugs or vaccines in order to control COVID-19. Since there is not a medication or vaccine for treating the disease and drug development project is a time and cost consuming process, drug repurposing approaches may yield to proper curing plans. However, there are some limitations in this field, which make the process a challenging one. This letter aims to introduce drug repurposing methods and the existing challenges to detect candidate drugs which may be helpful in controlling COVID-19.

PMID: 32793443 [PubMed]

Quinolines-Based SARS-CoV-2 3CLpro and RdRp Inhibitors and Spike-RBD-ACE2 Inhibitor for Drug-Repurposing Against COVID-19: An in silico Analysis.

Front Microbiol. 2020;11:1796

Authors: Alexpandi R, De Mesquita JF, Pandian SK, Ravi AV

Abstract
The novel coronavirus SARS-CoV-2 disease "COVID-19" emerged in China and rapidly spread to other countries; due to its rapid worldwide spread, the WHO has declared this as a global emergency. As there is no specific treatment prescribed to treat COVID-19, the seeking of suitable therapeutics among existing drugs seems valuable. The structure availability of coronavirus macromolecules has encouraged the finding of conceivable anti-SARS-CoV-2 therapeutics through in silico analysis. The results reveal that quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI) and saquinavir strongly interact with the active site (Cys-His catalytic dyad), thereby are predicted to hinder the activity of SARS-CoV-2 3CLpro. Out of 113 quinoline-drugs, elvitegravir and oxolinic acid are able to interact with the NTP entry-channel and thus interfere with the RNA-directed 5'-3' polymerase activity of SARS-CoV-2 RdRp. The bioactivity-prediction results also validate the outcome of the docking study. Moreover, as SARS-CoV-2 Spike-glycoprotein uses human ACE2-receptor for viral entry, targeting the Spike-RBD-ACE2 has been viewed as a promising strategy to control the infection. The result shows rilapladib is the only quinoline that can interrupt the Spike-RBD-ACE2 complex. In conclusion, owing to their ability to target functional macromolecules of SARS-CoV-2, along with positive ADMET properties, quinoline,1,2,3,4-tetrahydro-1-[(2-phenylcyclopropyl)sulfonyl]-trans-(8CI), saquinavir, elvitegravir, oxolinic acid, and rilapladib are suggested for the treatment of COVID-19.

PMID: 32793181 [PubMed]

Administration of small-molecule guanabenz acetate attenuates fatty liver and hyperglycemia associated with obesity.

Sci Rep. 2020 Aug 13;10(1):13671

Authors: Yoshino S, Iwasaki Y, Matsumoto S, Satoh T, Ozawa A, Yamada E, Kakizaki S, Trejo JAO, Uchiyama Y, Yamada M, Mori M

Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of hepatic triglycerides (TG) and hyperglycemia arising due to persistent insulin resistance, and is profoundly linked to obesity. However, there is currently no established treatment for NAFLD in obese human subjects. We previously isolated Helz2, the expression of which was upregulated in human and mouse NAFLD, and its deletion activated the hepatic expression of functional leptin receptor long form (Leprb) and suppressed NAFLD development and body weight (BW) gain in obese mice. A high-throughput assay of small-molecule drugs revealed that guanabenz acetate (Ga), originally used to treat hypertension, possesses a high affinity constant against HELZ2, and its administration activates LEPRB expression in HepG2 cells in vitro. The chronic oral administration of Ga shows the selective leptin sensitization in the liver via upregulation of hepatic Leprb expression, which affects expression of genes involved in lipogenesis and fatty acid β-oxidation and diminishes hepatocyte hypertrophy with droplets enriched in TG in high-fat diet-induced obese mice. This activity significantly improves insulin resistance to decrease hyperglycemia and hepatocyte and adipocyte weights, resulting in BW reduction without reducing food intake. Regarding drug repositioning, Ga has the potential to effectively treat NAFLD and hyperglycemia in obese patients.

PMID: 32792584 [PubMed - in process]

9 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 2020/08/14

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.