The role of growth factor receptors in viral infections: An opportunity for drug repurposing against emerging viral diseases such as COVID-19?

FASEB Bioadv. 2020 May;2(5):296-303

Authors: Hondermarck H, Bartlett NW, Nurcombe V

Abstract
Growth factor receptors are known to be involved in the process of viral infection. Many viruses not only use growth factor receptors to physically attach to the cell surface and internalize, but also divert receptor tyrosine kinase signaling in order to replicate. Thus, repurposing drugs that have initially been developed to target growth factor receptors and their signaling in cancer may prove to be a fast track to effective therapies against emerging new viral infections, including the coronavirus disease 19 (COVID-19).

PMID: 32395702 [PubMed]

Repurposing fenamic acids drugs to combat multidrug-resistant Neisseria gonorrhoeae.

Antimicrob Agents Chemother. 2020 May 11;:

Authors: Seong YJ, Alhashimi M, Mayhoub A, Mohammad H, Seleem MN

Abstract
The rise of extensive and multidrug-resistant strains of Neisseria gonorrhoeae has occurred in parallel with the increasing demand for new drugs. However, the current methods of drug discovery are burdened with rigorous assessments and requires more time than can be spared until gonococcal infections become hard to control. To address this urgency, we utilized a drug repurposing strategy and identified three clinically-approved anthranilic acid drugs (tolfenamic acid, flufenamic acid, and meclofenamic acid) with potent anti-gonococcal activity, inhibiting 50% of the strains (MIC50) from 4 to 16 μg/mL. Furthermore, tolfenamic acid showed an indifferent activity with antibiotics of choice for gonococcal infections, azithromycin and ceftriaxone, in checkerboard assays with a fractional inhibitory concentration index ranging from 0.75 to 1.5. Fenamic acids reduced a high inoculum of N. gonorrhoeae below the limit of detection within 12 hours and exhibited a low frequency of resistance. Interestingly, the fenamic acids did not inhibit growth of commensal Lactobacillus spp. that comprise the healthy female genital microbiota. Fenamic acids were also superior to ceftriaxone in reducing the burden of intracellular N. gonorrhoeae within infected endocervical cells by 99%. Furthermore, all three fenamic acids significantly reduced the expression of the porinflammatory cytokines by infected endocervical cells. Finally, fenamic acids and other structurally-related anthranilic acid derivatives were evaluated to ascertain a more in-depth structure activity relationship (SAR) that revealed N-phenylanthranilic acid as a novel anti-gonorrheal scaffold. This SAR study will pave the road to reposition more potent fenamic acids analogues against N. gonorrhoeae.

PMID: 32393483 [PubMed - as supplied by publisher]

Identification of clinically approved small molecules that inhibit growth and affect transcript levels of developmentally regulated genes in the African trypanosome.

PLoS Negl Trop Dis. 2020 03;14(3):e0007790

Authors: Walsh ME, Naudzius EM, Diaz SJ, Wismar TW, Martchenko Shilman M, Schulz D

Abstract
Trypanosoma brucei are unicellular parasites endemic to Sub-Saharan Africa that cause fatal disease in humans and animals. Infection with these parasites is caused by the bite of the tsetse fly vector, and parasites living extracellularly in the blood of infected animals evade the host immune system through antigenic variation. Existing drugs for Human and Animal African Trypanosomiasis are difficult to administer and can have serious side effects. Resistance to some drugs is also increasing, creating an urgent need for alternative trypanosomiasis therapeutics. We screened a library of 1,585 U.S. or foreign-approved drugs and identified 154 compounds that inhibit trypanosome growth. As all of these compounds have already undergone testing for human toxicity, they represent good candidates for repurposing as trypanosome therapeutics. In addition to identifying drugs that inhibit trypanosome growth, we wished to identify small molecules that can induce bloodstream form parasites to differentiate into forms adapted for the insect vector. These insect stage parasites lack the immune evasion mechanisms prevalent in bloodstream forms, making them vulnerable to the host immune system. To identify drugs that increase transcript levels of an invariant, insect-stage specific surface protein called procyclin, we engineered bloodstream reporter parasites that express Green Fluorescent Protein (GFP) following induction or stabilization of the procyclin transcript. Using these bloodstream reporter strains in combination with automated flow cytometry, we identified eflornithine, spironolactone, and phenothiazine as small molecules that increase abundance of procyclin transcript. Both eflornithine and spironolactone also affect transcript levels for a subset of differentiation associated genes. While we failed to identify compounds that increase levels of procyclin protein on the cell surface, this study is proof of principle that these fluorescent reporter parasites represent a useful tool for future small molecule or genetic screens aimed at identifying molecules or processes that initiate remodeling of the parasite surface during life cycle stage transitions.

PMID: 32168320 [PubMed - indexed for MEDLINE]

Antibiofilm and antibacterial activities of repurposing auranofin against Bacteroides fragilis.

Arch Microbiol. 2020 Apr;202(3):473-482

Authors: Jang HI, Eom YB

Abstract
The aim of this study is to evaluate the antibiofilm and antibacterial effects of auranofin against WT-ETBF, rETBF, WT-NTBF and clinically isolated Bacteroides fragilis strains. The minimum inhibitory concentration and biofilm inhibitory concentration of 0.25 μg/ml for auranofin against B. fragilis were determined, and the biofilm eradication concentration was 1 μg/ml. At an auranofin concentration of 0.5 μg/ml, little cellular metabolic activity was found. Confocal laser scanning microcopy results confirmed the inhibition of biofilm by auranofin. The effects of auranofin on the outer membrane protein (ompA) gene and the RND-type efflux pump (bmeB3) gene were investigated using quantitative real-time polymerase chain reaction (qRT-PCR). The qRT-PCR results showed that treatment with auranofin significantly reduced the gene expression compared to controls without auranofin. These data indicate the applicability of auranofin as a repurposed drug due to its inhibitory effect against biofilm formation of B. fragilis. Therefore, our study demonstrates that auranofin, already approved for human use, is a promising drug that has strong antibiofilm and antibacterial activity against B. fragilis.

PMID: 31705142 [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 2020/05/12

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.

Genomics of Blood Pressure and Hypertension: Extending the Mosaic Theory Toward Stratification.

Can J Cardiol. 2020 May;36(5):694-705

Authors: Lip S, Padmanabhan S

Abstract
The genetic architecture of blood pressure (BP) now includes more than 30 genes, with rare mutations resulting in inherited forms of hypertension or hypotension, and 1477 common single-nucleotide polymorphisms (SNPs). These signify the heterogeneity of the BP phenotype and support the mosaic theory of hypertension. The majority of monogenic syndromes involve the renin-angiotensin-aldosterone system and the adrenal glucocorticoid pathway, and a smaller fraction are due to rare neuroendocrine tumours of the adrenal glands and the sympathetic and parasympathetic paraganglia. Somatic mutations in genes coding for ion channels (KCNJ5 and CACNA1D) and adenosine triphosphatases (ATP1A1 and ATP2B3) highlight the central role of calcium signalling in autonomous aldosterone production by the adrenal gland. The per-SNP BP effect is small for SNPs according to genome-wide association studies (GWAS), and all of the GWAS-identified BP SNPs explain ∼ 27% of the 30%-50% estimated heritability of BP. Uromodulin is a novel pathway identified by GWAS, and it has now progressed to a genotype-directed clinical trial. The majority of the GWAS-identified BP SNPs show pleiotropic associations, and unravelling those signals and underpinning biological pathways offers potential opportunities for drug repurposing. The GWAS signals are predominantly from Europe-centric studies with other ancestries underrepresented, however, limiting the generalisability of the findings. In this review, we leverage the burgeoning list of polygenic and monogenic variants associated with BP regulation along with phenome-wide studies in the context of the mosaic theory of hypertension, and we explore potential translational aspects that underlie different hypertension subtypes.

PMID: 32389342 [PubMed - in process]

COVID-19: Living through Another Pandemic.

ACS Infect Dis. 2020 May 10;:

Authors: Osman EEA, Toogood PL, Neamati N

Abstract
Novel beta-coronavirus SARS-CoV-2 is the pathogenic agent responsible for coronavirus disease-2019 (COVID-19), a globally pandemic infectious disease. Due to its high virulence and the absence of immunity among the general population, SARS-CoV-2 has quickly spread to all countries. This pandemic highlights the urgent unmet need to expand and focus our research tools on what are considered "neglected infectious diseases" and to prepare for future inevitable pandemics. This global emergency has generated unprecedented momentum and scientific efforts around the globe unifying scientists from academia, government and the pharmaceutical industry to accelerate the discovery of vaccines and treatments. Herein, we shed light on the virus structure and life cycle and the potential therapeutic targets in SARS-CoV-2 and briefly refer to both active and passive immunization modalities, drug repurposing focused on speed to market, and novel agents against specific viral targets as therapeutic interventions for COVID-19.

PMID: 32388976 [PubMed - as supplied by publisher]

SARS-CoV-2 RNA polymerase as target for antiviral therapy.

J Transl Med. 2020 05 05;18(1):185

Authors: Buonaguro L, Tagliamonte M, Tornesello ML, Buonaguro FM

Abstract
A new human coronavirus named SARS-CoV-2 was identified in several cases of acute respiratory syndrome in Wuhan, China in December 2019. On March 11 2020, WHO declared the SARS-CoV-2 infection to be a pandemic, based on the involvement of 169 nations. Specific drugs for SARS-CoV-2 are obviously not available. Currently, drugs originally developed for other viruses or parasites are currently in clinical trials based on empiric data. In the quest of an effective antiviral drug, the most specific target for an RNA virus is the RNA-dependent RNA-polymerase (RdRp) which shows significant differences between positive-sense and negative-sense RNA viruses. An accurate evaluation of RdRps from different viruses may guide the development of new drugs or the repositioning of already approved antiviral drugs as treatment of SARS-CoV-2. This can accelerate the containment of the SARS-CoV-2 pandemic and, hopefully, of future pandemics due to other emerging zoonotic RNA viruses.

PMID: 32370758 [PubMed - indexed for MEDLINE]

Beyond depression: Other uses for tricyclic antidepressants.

Cleve Clin J Med. 2019 12;86(12):807-814

Authors: Schneider J, Patterson M, Jimenez XF

Abstract
Tricyclic antidepressants (TCAs) were originally designed and marketed for treating depression, but over time they have been applied to a variety of conditions, mostly off-label. TCAs can serve as first-line or augmenting drugs for neuropathic pain, headache, migraine, gastrointestinal syndromes, fibromyalgia, pelvic pain, insomnia, and psychiatric conditions other than depression. This article reviews pharmacology, dosing, and safety considerations for these uses.

PMID: 31821138 [PubMed - indexed for MEDLINE]

Diabetes Therapies for Dementia.

Curr Neurol Neurosci Rep. 2019 07 12;19(8):58

Authors: Moran C, Callisaya ML, Srikanth V, Arvanitakis Z

Abstract
PURPOSE OF REVIEW: Type 2 diabetes (T2D) is a well-established risk factor for the development of dementia. Dementia and T2D share some underlying pathophysiology that has led to interest in the potential to repurpose drugs used in the management of T2D to benefit brain health. This review describes the scientific data available on the use of T2D medications for the risk reduction or management of dementia, in people with and without T2D.
RECENT FINDINGS: Results from basic laboratory research support the potential for commonly-used medications for T2D, including those with direct glucose-lowering properties, to have a beneficial effect on brain health. However, human studies have been mostly observational in nature and report conflicting results. Preliminary data suggest that intranasal insulin, metformin, and GLP-1 agonists show promise for dementia, but confirmatory evidence for their benefit in dementia is still lacking. Current evidence does not support the repurposing of T2D medications for dementia risk reduction or management. Research in the field of T2D and dementia is active, and further data are required before definitive conclusions can be drawn.

PMID: 31300920 [PubMed - indexed for MEDLINE]

Connectivity map-based drug repositioning of bortezomib to reverse the metastatic effect of GALNT14 in lung cancer.

Oncogene. 2020 May 09;:

Authors: Kwon OS, Lee H, Kong HJ, Kwon EJ, Park JE, Lee W, Kang S, Kim M, Kim W, Cha HJ

Abstract
Despite the continual discovery of promising new cancer targets, drug discovery is often hampered by the poor druggability of these targets. As such, repurposing FDA-approved drugs based on cancer signatures is a useful alternative to cancer precision medicine. Here, we adopted an in silico approach based on large-scale gene expression signatures to identify drug candidates for lung cancer metastasis. Our clinicogenomic analysis identified GALNT14 as a putative driver of lung cancer metastasis, leading to poor survival. To overcome the poor druggability of GALNT14 in the control of metastasis, we utilized the Connectivity Map and identified bortezomib (BTZ) as a potent metastatic inhibitor, bypassing the direct inhibition of the enzymatic activity of GALNT14. The antimetastatic effect of BTZ was verified both in vitro and in vivo. Notably, both BTZ treatment and GALNT14 knockdown attenuated TGFβ-mediated gene expression and suppressed TGFβ-dependent metastatic genes. These results demonstrate that our in silico approach is a viable strategy for the use of undruggable targets in cancer therapies and for revealing the underlying mechanisms of these targets.

PMID: 32388539 [PubMed - as supplied by publisher]

Sofosbuvir as Repurposed Antiviral Drug Against COVID-19: Why Were We Convinced to Evaluate the Drug in a Registered/Approved Clinical Trial?

Arch Med Res. 2020 Apr 29;:

Authors: Sayad B, Sobhani M, Khodarahmi R

Abstract
COVID-19 is a devastating global pandemic around the world. While the majority of infected cases appear mild, in some cases individuals present respiratory complications with possible serious lung damage. There are no specific treatments for COVID-19 as yet, though a number are under evaluation, including experimental antivirals. Sofosbuvir, the clinically approved anti-hepatitis C virus (HCV) drug, is also capable of suppressing other families of positive-strand RNA viruses; Flaviviridae and Togaviridae. Coronaviruses are a family of positive-strand RNA viruses with conserved polymerase, so SARS-CoV-2 RdRp is very likely to be effectively inhibited by sofosbuvir. More importantly, sofosbuvir is safe and well tolerated at 400 mg daily in a 24 week therapeutic regimen. Sofosbuvir active metabolite, however, shows an extremely high intracellular stability So, it is hypothesized that SARS-CoV-2 infection could also be susceptible to sofosbuvir and we were convinced to design and run a clinical trial to evaluate the effect of sofosbuvir 400 mg (in combination with velpatasvir 100 mg, as add-on treatment, in addition to standard of care) on the COVID-19. However, we believe that this manuscript/correspondence should be made available to the international scientific community as soon as possible, with the help of this esteemed journal.

PMID: 32387040 [PubMed - as supplied by publisher]

Drug repurposing in cardiology.

Neth Heart J. 2020 May 06;:1-2

Authors: van Driel BO, van der Velden J

PMID: 32382255 [PubMed - as supplied by publisher]

Repurposing Zileuton as a Depression Drug Using an AI and In Vitro Approach.

Molecules. 2020 May 05;25(9):

Authors: Kubick N, Pajares M, Enache I, Manda G, Mickael ME

Abstract
Repurposing drugs to target M1 macrophages inflammatory response in depression constitutes a bright alternative for commonly used antidepressants. Depression is a significant type of mood disorder, where patients suffer from pathological disturbances associated with a proinflammatory M1 macrophage phenotype. Presently, the most commonly used antidepressants such as Zoloft and Citalopram can reduce inflammation, but suffer from dangerous side effects without offering specificity toward macrophages. We employed a new strategy for drug repurposing based on the integration of RNA-seq analysis and text mining using deep neural networks. Our system employs a Google semantic AI universal encoder to compute sentences embedding. Sentences similarity is calculated using a sorting function to identify drug compounds. Then sentence relevance is computed using a custom-built convolution differential network. Our system highlighted the NRF2 pathway as a critical drug target to reprogram M1 macrophage response toward an anti-inflammatory profile (M2). Using our approach, we were also able to predict that lipoxygenase inhibitor drug zileuton could modulate NRF2 pathway in vitro. Taken together, our results indicate that reorienting zileuton usage to modulate M1 macrophages could be a novel and safer therapeutic option for treating depression.

PMID: 32380663 [PubMed - in process]

Repurposing of drugs: An attractive pharmacological strategy for cancer therapeutics.

Semin Cancer Biol. 2020 May 04;:

Authors: Kirtonia A, Gala K, Fernandes SG, Pandya G, Pandey AK, Sethi G, Khattar E, Garg M

Abstract
Human malignancies are one of the major health-related issues though out the world and anticipated to rise in the future. The development of novel drugs/agents requires a huge amount of cost and time that represents a major challenge for drug discovery. In the last three decades, the number of FDA approved drugs has dropped down and this led to increasing interest in drug reposition or repurposing. The present review focuses on recent concepts and therapeutic opportunities for the utilization of antidiabetics, antibiotics, antifungal, anti-inflammatory, antipsychotic, PDE inhibitors and estrogen receptor antagonist, Antabuse, antiparasitic and cardiovascular agents/drugs as an alternative approach against human malignancies. The repurposing of approved non-cancerous drugs is an effective strategy to develop new therapeutic options for the treatment of cancer patients at an affordable cost in clinics. In the current scenario, most of the countries throughout the globe are unable to meet the medical needs of cancer patients because of the high cost of the available cancerous drugs. Some of these drugs displayed potential anti-cancer activity in preclinic and clinical studies by regulating several key molecular mechanisms and oncogenic pathways in human malignancies. The emerging pieces of evidence indicate that repurposing of drugs is crucial to the faster and cheaper discovery of anti-cancerous drugs.

PMID: 32380233 [PubMed - as supplied by publisher]

Alphavirus capsid protease inhibitors as potential antiviral agents for Chikungunya infection.

Antiviral Res. 2020 May 04;:104808

Authors: Fatma B, Kumar R, Singh VA, Nehul S, Sharma R, Kesari P, Kuhn RJ, Tomar S

Abstract
Chikungunya virus (CHIKV) is an arthritogenic alphavirus and currently, no antiviral drug is available to combat it. Capsid protein (CP) of alphaviruses present at the N-terminus of the structural polyprotein possesses auto-proteolytic activity which is essential for initiating the structural polyprotein processing. We are reporting for the first time antiviral molecules targeting capsid proteolytic activity. Structure-assisted drug-repositioning identified three molecules: P1P4 Diadenosine tetraphosphate (AP4), Eptifibatide acetate (EAC) and Paromomycin sulphate (PSU) as potential capsid protease inhibitors. A FRET-based proteolytic assay confirmed anti-proteolytic activity of these molecules. Additionally, in vitro cell-based antiviral studies showed that EAC, AP4, and PSU drastically stifled CHIKV at the post-entry step with a half-maximal effective concentration (EC50) of 4.01 μM, 10.66 μM and 22.91 μM respectively. Interestingly, the inhibitors had no adverse effect on viral RNA synthesis and treatment of cells with inhibitors diminished levels of CP in virus-infected cells, which confirmed inhibition of capsid auto-proteolytic activity. In conclusion, the discovery of antiviral molecules targeting capsid protease demystifies the alphavirus capsid protease as a potential target for antiviral drug discovery.

PMID: 32380148 [PubMed - as supplied by publisher]

Knowledge-based structural models of SARS-CoV-2 proteins and their complexes with potential drugs.

FEBS Lett. 2020 May 07;:

Authors: Hijikata A, Shionyu-Mitsuyama C, Nakae S, Shionyu M, Ota M, Kanaya S, Shirai T

Abstract
The World Health Organization (WHO) has declared the coronavirus disease 2019 (COVID-19) caused by the novel coronavirus SARS-CoV-2 a pandemic. There is, however, no confirmed anti-COVID-19 therapeutic currently. In order to assist structure-based discovery efforts for repurposing drugs against this disease, we constructed knowledge-based models of SARS-CoV-2 proteins and compared the ligand molecules in the template structures with approved/experimental drugs and components of natural medicines. Our theoretical models suggest several drugs, such as carfilzomib, sinefungin, tecadenoson, and trabodenoson, that could be further investigated for their potential for treating COVID-19.

PMID: 32379896 [PubMed - as supplied by publisher]

Drug repurposing in cardiology.

Neth Heart J. 2020 May 06;:

Authors: van Driel BO, van der Velden J

PMID: 32378128 [PubMed - as supplied by publisher]

Perphenazine Attenuates the Pro-Inflammatory Responses in Mouse Models of Th2-Type Allergic Dermatitis.

Int J Mol Sci. 2020 May 03;21(9):

Authors: Heo MJ, Choi SY, Lee C, Choi YM, An IS, Bae S, An S, Jung JH

Abstract
Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect. Two different animal models including 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA)-induced dermatitis were employed. TPA and OXA-mediated ear swelling was attenuated by perphenazine. Moreover, perphenazine inhibited infiltrated mast cells into lesion area. We found levels of serum IgE, histamine and cytokines are decreased in mice cotreated with perphenazine and OXA compared to OXA-treated mice. Overall, this is a first study showing that the FDA-approved, anti-psychotic drug, perphenazine, alleviates animal models of dermatitis.

PMID: 32375285 [PubMed - in process]

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 2020/05/07

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.