Are Myths and Preconceptions Preventing us from Applying Ionic Liquid Forms of Antiviral Medicines to the Current Health Crisis?

Int J Mol Sci. 2020 Aug 20;21(17):

Authors: Shamshina JL, Rogers RD

Abstract
At the moment, there are no U.S. Food and Drug Administration (U.S. FDA)-approved drugs for the treatment of COVID-19, although several antiviral drugs are available for repurposing. Many of these drugs suffer from polymorphic transformations with changes in the drug's safety and efficacy; many are poorly soluble, poorly bioavailable drugs. Current tools to reformulate antiviral APIs into safer and more bioavailable forms include pharmaceutical salts and cocrystals, even though it is difficult to classify solid forms into these regulatory-wise mutually exclusive categories. Pure liquid salt forms of APIs, ionic liquids that incorporate APIs into their structures (API-ILs) present all the advantages that salt forms provide from a pharmaceutical standpoint, without being subject to solid-state matter problems. In this perspective article, the myths and the most voiced concerns holding back implementation of API-ILs are examined, and two case studies of API-ILs antivirals (the amphoteric acyclovir and GSK2838232) are presented in detail, with a focus on drug property improvement. We advocate that the industry should consider the advantages of API-ILs which could be the genesis of disruptive innovation and believe that in order for the industry to grow and develop, the industry should be comfortable with a certain element of risk because progress often only comes from trying something different.

PMID: 32825444 [PubMed - indexed for MEDLINE]

Putative SARS-CoV-2 Mpro Inhibitors from an In-House Library of Natural and Nature-Inspired Products: A Virtual Screening and Molecular Docking Study.

Molecules. 2020 Aug 17;25(16):

Authors: Mazzini S, Musso L, Dallavalle S, Artali R

Abstract
A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been the cause of a recent global pandemic. The highly contagious nature of this life-threatening virus makes it imperative to find therapies to counteract its diffusion. The main protease (Mpro) of SARS-CoV-2 is a promising drug target due to its indispensable role in viral replication inside the host. Using a combined two-steps approach of virtual screening and molecular docking techniques, we have screened an in-house collection of small molecules, mainly composed of natural and nature-inspired compounds. The molecules were selected with high structural diversity to cover a wide range of chemical space into the enzyme pockets. Virtual screening experiments were performed using the blind docking mode of the AutoDock Vina software. Virtual screening allowed the selection of structurally heterogeneous compounds capable of interacting effectively with the enzymatic site of SARS-CoV-2 Mpro. The compounds showing the best interaction with the protein were re-scored by molecular docking as implemented in AutoDock, while the stability of the complexes was tested by molecular dynamics. The most promising candidates revealed a good ability to fit into the protein binding pocket and to reach the catalytic dyad. There is a high probability that at least one of the selected scaffolds could be promising for further research.

PMID: 32824454 [PubMed - indexed for MEDLINE]

Niclosamide repurposed for the treatment of inflammatory airway disease.

JCI Insight. 2019 08 08;4(15):

Authors: Cabrita I, Benedetto R, Schreiber R, Kunzelmann K

Abstract
Inflammatory airway diseases, such as asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD), are characterized by mucus hypersecretion and airway plugging. In both CF and asthma, enhanced expression of the Ca2+-activated Cl- channel TMEM16A is detected in mucus-producing club/goblet cells and airway smooth muscle. TMEM16A contributes to mucus hypersecretion and bronchoconstriction, which are both inhibited by blockers of TMEM16A, such as niflumic acid. Here we demonstrate that the FDA-approved drug niclosamide, a potent inhibitor of TMEM16A identified by high-throughput screening, is an inhibitor of both TMEM16A and TMEM16F. In asthmatic mice, niclosamide reduced mucus production and secretion, as well as bronchoconstriction, and showed additional antiinflammatory effects. Using transgenic asthmatic mice, we found evidence that TMEM16A and TMEM16F are required for normal mucus production/secretion, which may be due to their effects on intracellular Ca2+ signaling. TMEM16A and TMEM16F support exocytic release of mucus and inflammatory mediators, both of which are blocked by niclosamide. Thus, inhibition of mucus and cytokine release, bronchorelaxation, and reported antibacterial effects make niclosamide a potentially suitable drug for the treatment of inflammatory airway diseases, such as CF, asthma, and COPD.

PMID: 31391337 [PubMed - indexed for MEDLINE]

COVID-19 drug repurposing: A review of computational screening methods, clinical trials, and protein interaction assays.

Med Res Rev. 2020 Aug 30;:

Authors: Wang X, Guan Y

Abstract
The situation of coronavirus disease 2019 (COVID-19) pandemic is rapidly evolving, and medical researchers around the globe are dedicated to finding cures for the disease. Drug repurposing, as an efficient way for drug development, has received a lot of attention. However, the huge amount of studies makes it challenging to keep up to date with the literature on COVID-19 therapeutic development. This review addresses this challenge by grouping the COVID-19 drug repurposing research into three large groups, including clinical trials, computational research, and in vitro protein-binding experiments. Particularly, to facilitate future drug discovery and the creation of effective drug combinations, drugs are organized by their mechanisms of action and reviewed by their efficacy measured by clinical trials. Providing this subtyping information, we hope this review would serve the scientists, clinicians, and the pharmaceutical industry who are looking at the new therapeutics for COVID-19 treatment.

PMID: 32864815 [PubMed - as supplied by publisher]

Whole transcriptome in silico screening implicates cardiovascular and infectious disease in the mechanism of action underlying atypical antipsychotic side effects.

Alzheimers Dement (N Y). 2020;6(1):e12078

Authors: Malekizadeh Y, Williams G, Kelson M, Whitfield D, Mill J, Collier DA, Ballard C, Jeffries AR, Creese B

Abstract
Background: Stroke/thromboembolic events, infections, and death are all significantly increased by antipsychotics in dementia but little is known about why they can be harmful. Using a novel application of a drug repurposing paradigm, we aimed to identify potential mechanisms underlying adverse events.
Methods: Whole transcriptome signatures were generated for SH-SY5Y cells treated with amisulpride, risperidone, and volinanserin using RNA sequencing. Bioinformatic analysis was performed that scored the association between antipsychotic signatures and expression data from 415,252 samples in the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) repository.
Results: Atherosclerosis, venous thromboembolism, and influenza NCBI GEO-derived samples scored positively against antipsychotic signatures. Pathways enriched in antipsychotic signatures were linked to the cardiovascular and immune systems (eg, brain derived neurotrophic factor [BDNF], platelet derived growth factor receptor [PDGFR]-beta, tumor necrosis factor [TNF], transforming growth factor [TGF]-beta, selenoamino acid metabolism, and influenza infection).
Conclusions: These findings for the first time mechanistically link antipsychotics to specific cardiovascular and infectious diseases which are known side effects of their use in dementia, providing new information to explain related adverse events.

PMID: 32864416 [PubMed]

Ivermectin: Potential Role as Repurposed Drug for COVID-19.

Malays J Med Sci. 2020 Jul;27(4):154-158

Authors: Dixit A, Yadav R, Singh AV

Abstract
Severe acute respiratory illness caused by 2019 novel coronavirus (2019-nCoV), officially named severe acute respiratory syndrome coronavirus (SARS-CoV-2) in late December 2019 is an extremely communicable disease. World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a pandemic as it has spread to at least 200 countries in a short span of time. Being a new disease there is lack of information about pathogenesis and proliferation pathways of this new coronavirus. Currently there is no effective treatment for coronavirus infection; major effort is to develop vaccine against the virus and development of therapeutic drugs for the disease. The development of genome-based vaccine and therapeutic antibodies require thorough testing for safety and will be available after some time. In the meanwhile, the available practical approach is to repurpose existing therapeutic agents, with proven safety record as a rapid response measure for the current pandemic. Here we discuss the presently used repurposed drugs for COVID-19 and the potential for ivermectin (IVM) to be used as a therapeutic option in COVID-19.

PMID: 32863755 [PubMed]

Bexarotene combined with lapatinib for the treatment of Cushing's disease: evidence based on drug repositioning and experimental confirmation.

Signal Transduct Target Ther. 2020 Aug 29;5(1):175

Authors: Yu H, Ren S, Wang J, Lv T, Sun L, Du G

PMID: 32862196 [PubMed - in process]

The past, present and future of RNA respiratory viruses: Influenza and coronaviruses.

Pathog Dis. 2020 Aug 29;:

Authors: Makarov V, Riabova O, Ekins S, Pluzhnikov N, Chepur S

Abstract
Influenza virus and coronaviruses continue to cause pandemics across the globe. We know have a greater understanding of their function. Unfortunately the number of drugs in our armory to defend us against them are inadequate. This may require us to think about what mechanisms to address. We now review the biological properties of these viruses, their genetic evolution and antiviral therapies that can be used or have been attempted. We will describe several classes of drugs such as serine protease inhibitors, heparin, and heparan sulphate receptor inhibitors, chelating agents, immunomodulators and many others. We also briefly describe some of the drug repurposing efforts which have taken place in an effort to rapidly identify molecules to treat patients with COVID-19. While we have a heavy emphasis on the past and present efforts, we also provide some thoughts about what we need to do to prepare for respiratory viral threats in the future.

PMID: 32860686 [PubMed - as supplied by publisher]

To Be Continued? Long-Term Treatment Effects of Antidepressant Drug Classes and Individual Antidepressants on the Risk of Developing Dementia: A German Case-Control Study.

J Clin Psychiatry. 2020 Aug 25;81(5):

Authors: Bartels C, Belz M, Vogelgsang J, Hessmann P, Bohlken J, Wiltfang J, Kostev K

Abstract
BACKGROUND: Given the need for disease-modifying therapies for dementia, drug repurposing appears to be a promising approach, at least as a risk reduction treatment. Preclinical studies suggest that antidepressants-in particular selective serotonin reuptake inhibitors-have beneficial effects on dementia-related biomarkers and functional outcomes, although clinical data are inconclusive. The present case-control study aimed to evaluate the effects of antidepressant drug classes and individual compounds with different treatment durations on the risk of developing dementia.
METHODS: Analyses are based on data from the German Disease Analyzer database (owned and maintained by IQVIA) and included 62,317 subjects with an incident dementia diagnosis (ICD-10: F01, F03, G30, F06.7) and controls matched by age, sex, and physician between January 2013 and December 2017. Logistic regression analyses adjusting for health insurance status and comorbid diseases associated with dementia or antidepressant use were performed to investigate the association between dementia incidence and treatment with 4 major antidepressant drug classes and 14 of the most frequently prescribed individual substances.
RESULTS: In 17 of 18 comparisons, long-term treatment (≥ 2 years) with any antidepressant was associated with a lower incidence of dementia than short-term treatment. Tricyclic and herbal antidepressants were associated with a decrease in dementia incidence, especially with long-term treatment. The lowest risks for dementia on an individual substance basis were identified for long-term treatment with escitalopram (odds ratio [OR] = 0.66; 95% CI, 0.50-0.89) and Hypericum perforatum (OR = 0.6; 95% CI, 0.51-0.70).
CONCLUSIONS: Long-term treatment with tricyclic antidepressants, Hypericum perforatum, or escitalopram may be associated with reduced incidence of dementia. If antidepressant therapy is well tolerated, continuation-even if depressive symptoms have resolved-may be considered even beyond the purpose of relapse prevention. Future combined analyses of multinational registries and long-term clinical trials are needed to substantiate these findings.

PMID: 32857931 [PubMed - as supplied by publisher]

Coronavirus Disease-2019 Treatment Strategies Targeting Interleukin-6 Signaling and Herbal Medicine.

OMICS. 2020 Aug 26;:

Authors: Dzobo K, Chiririwa H, Dandara C, Dzobo W

Abstract
Coronavirus disease-2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is evolving across the world and new treatments are urgently needed as with vaccines to prevent the illness and stem the contagion. The virus affects not only the lungs but also other tissues, thus lending support to the idea that COVID-19 is a systemic disease. The current vaccine and treatment development strategies ought to consider such systems medicine perspectives rather than a narrower focus on the lung infection only. COVID-19 is associated with elevated levels of the inflammatory cytokines such as interleukin-6 (IL-6), IL-10, and interferon-gamma (IFN-γ). Elevated levels of cytokines and the cytokine storm have been linked to fatal disease. This suggests new therapeutic strategies through blocking the cytokine storm. IL-6 is one of the major cytokines associated with the cytokine storm. IL-6 is also known to display pleiotropic/diverse pathophysiological effects. We suggest the blockage of IL-6 signaling and its downstream mediators such as Janus kinases (JAKs), and signal transducer and activators of transcription (STATs) offer potential hope for the treatment of severe cases of COVID-19. Thus, repurposing of already approved IL-6-JAK-STAT signaling inhibitors as well as other anti-inflammatory drugs, including dexamethasone, is under development for severe COVID-19 cases. We conclude this expert review by highlighting the potential role of precision herbal medicines, for example, the Cannabis sativa, provided that omics technologies can be utilized to build a robust scientific evidence base on their clinical safety and efficacy. Precision herbal medicine buttressed by omics systems science would also help identify new molecular targets for drug discovery against COVID-19.

PMID: 32857671 [PubMed - as supplied by publisher]

Targeted Therapy for Chronıc Spontaneous Urtıcarıa: Ratıonale and Recent Progress.

Drugs. 2020 Aug 28;:

Authors: Giménez-Arnau AM, Salman A

Abstract
Chronic spontaneous urticaria (CSU) is characterized by the presence of wheals, angioedema, or both for at least 6 weeks. It may persist for a long time-up to 50% of the patients have been reported to be symptomatic 5 years after the onset. Some patients can suffer more than one episode of CSU during their lifetime. Considering the recurrences, disabling symptoms, and significant impact on quality of life, proper and effective treatment of CSU is critical. The use of antihistamines (AHs) is still the mainstay of treatment. However, given the low rates of response to AHs (38.6% and 63.2% to standard doses and higher doses, respectively), the complete control of symptoms seems difficult to attain. The use of omalizumab for CSU has been a major breakthrough in the care of patients with CSU. However, the partial response and lack of response to omalizumab in a subgroup of patients, as high as 70% in some studies, make the development of alternative treatments desirable. Ever-increasing knowledge on the pathogenesis is making new target molecules available and enabling drug development for CSU. In addition to drug repurposing as in anti-IL-4/13, IL-5, and IL-17 antibodies, novel targeted therapy options such as ligelizumab and Bruton's tyrosine kinase inhibitors are currently undergoing clinical trials and will be available in the near future. This article reviews the current challenges in the treatment of CSU, the pathogenesis and potential target molecules, and the rationale for novel treatments and their rapidly developing status.

PMID: 32857360 [PubMed - as supplied by publisher]

Coupled immune stratification and identification of therapeutic candidates in patients with lung adenocarcinoma.

Aging (Albany NY). 2020 Aug 27;12:

Authors: Hu W, Wang G, Chen Y, Yarmus LB, Liu B, Wan Y

Abstract
In recent years, personalized cancer immunotherapy, especially stratification-driven precision treatments have gained significant traction. However, due to the heterogeneity in clinical cohorts, the uncombined analysis of stratification/therapeutics may lead to confusion in determining ideal therapeutic options. We report that the coupled immune stratification and drug repurposing could facilitate identification of therapeutic candidates in patients with lung adenocarcinoma (LUAD). First, we categorized the patients into four groups based on immune gene profiling, associated with distinct molecular characteristics and clinical outcomes. Then, the weighted gene co-expression network analysis (WGCNA) algorithm was used to identify co-expression modules of each groups. We focused on C3 group which is characterized by low immune infiltration (cold tumor) and wild-type EGFR, posing a significant challenge for treatment of LUAD. Five drug candidates against the C3 status were identified which have potential dual functions to correct aberrant immune microenvironment and also halt tumorigenesis. Furthermore, their steady binding affinity against the targets was verified through molecular docking analysis. In sum, our findings suggest that such coupled analysis could be a promising methodology for identification and exploration of therapeutic candidates in the practice of personalized immunotherapy.

PMID: 32855362 [PubMed - as supplied by publisher]

Repurposing erectile dysfunction drugs tadalafil and vardenafil to increase bone mass.

Proc Natl Acad Sci U S A. 2020 06 23;117(25):14386-14394

Authors: Kim SM, Taneja C, Perez-Pena H, Ryu V, Gumerova A, Li W, Ahmad N, Zhu LL, Liu P, Mathew M, Korkmaz F, Gera S, Sant D, Hadelia E, Ievleva K, Kuo TC, Miyashita H, Liu L, Tourkova I, Stanley S, Lizneva D, Iqbal J, Sun L, Tamler R, Blair HC, New MI, Haider S, Yuen T, Zaidi M

Abstract
We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

PMID: 32513693 [PubMed - indexed for MEDLINE]

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Peptide-lipid nanoconstructs act site-specifically towards glioblastoma growth impairment.

Eur J Pharm Biopharm. 2020 Aug 20;:

Authors: Basso J, Mendes M, Silva J, Sereno J, Cova T, Oliveira R, Fortuna A, Castelo-Branco M, Falcão A, Sousa J, Pais A, Vitorino C

Abstract
Ultra-small nanostructured lipid carriers (usNLCs) have been hypothesized to promote site-specific glioblastoma (GB) drug delivery. Envisioning a multitarget purpose towards tumor cells and microenvironment, a surface-bioconjugated usNLC prototype is herein presented. The comeback of co-delivery by repurposing atorvastatin and curcumin, as complementary therapy, was unveiled and characterized, considering colloidal properties, stability, and drug release behavior. Specifically, the impact of the surface modification of usNLCs with hyaluronic acid (HA) conjugates bearing the cRGDfK and H7k(R2)2 peptides, and folic acid (FA) on GB cells was sequentially evaluated, in terms of cytotoxicity, internalization, uptake mechanism and hemolytic character. As proof-of-principle, the biodistribution, tolerability, and efficacy of the nanocarriers were assessed, the latter in GB-bearing mice through magnetic resonance imaging and spectroscopy. The hierarchical modification of the usNLCs promotes a preferential targeting behavior to the brain, while simultaneously sparing the elimination by clearance organs. Moreover, usNLCs were found to be well tolerated by mice and able to impair tumor growth in an orthotopic xenograft model, whereas for mice administered with the non-encapsulated therapeutic compounds, tumor growth exceeded 181% in the same period. Relevant biomarkers extracted from metabolic spectroscopy were ultimately identified as a potential tumor signature.

PMID: 32828948 [PubMed - as supplied by publisher]

Emerging strategies on in silico drug development against COVID-19: challenges and opportunities.

Eur J Pharm Sci. 2020 Aug 19;:105522

Authors: Yadav M, Dhagat S, Eswari JS

Abstract
The importance of coronaviruses as human pathogen has been highlighted by the recent outbreak of SARS-CoV-2 leading to the search of suitable drugs to overcome respiratory infections caused by the virus. Due to the lack of specific drugs against coronavirus, the existing antiviral and antimalarial drugs are currently being administered to the patients infected with SARS-CoV-2. The scientists are also considering repurposing of some of the existing drugs as a suitable option in search of effective drugs against coronavirus till the establishment of a potent drug and/or vaccine. Computer-aided drug discovery provides a promising attempt to enable scientists to develop new and target specific drugs to combat any disease. The discovery of novel targets for COVID-19 using computer-aided drug discovery tools requires the knowledge of structure of the coronavirus and the various target proteins present in the virus. Targeting the viral proteins will make the drug specific against the virus, thereby, increasing the chances of viral mortality. Hence, this review provides the structure of SARS-CoV-2 virus along with the important viral components involved in causing infection. It also focuses on the role of various target proteins in disease, the mechanism by which currently administered drugs act against the virus and the repurposing of few drugs. The gap arising from the absence of specific drugs is addressed by proposing potential antiviral drug targets which might provide insights into structure-based drug development against SARS-CoV-2.

PMID: 32827661 [PubMed - as supplied by publisher]