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NAFLD is the most common cause of liver disease worldwide, and its prevalence is significantly increasing. Studies have shown that it is associated with comorbidities such as diabetes, metabolic syndrome and obesity. Early diagnosis and management are highly important and could modify the prognosis of the disease. Evaluating the possibility of multiple aetiologies and recognizing the additional causes of liver disease should be a part of the patient's initial assessment. There are no approved drug treatments as yet, so the main management strategies should involve lifestyle changes such as physical activity and dietary re-education.

The dramatic increase in antimicrobial resistance and the limited pharmacological treatment options highlight the urgent need to optimize therapeutic regimens of new and available anti-infectives. Several in-vitro and in-vivo infection models are employed to understand the relationship between drug exposure profiles in plasma or at the site of infection (pharmacokinetics) and the time course of therapeutic response (pharmacodynamics) to select and optimize dosage regimens for new and approved drugs. Well-designed preclinical studies, combined with mathematical-model-based pharmacokinetic/pharmacodynamic analysis and in-silico simulations, are critical for the effective translation of preclinical data and design of appropriate and successful clinical trials. Integration with population pharmacokinetic modelling and simulations allows for the incorporation of interindividual variability that occurs in both pharmacokinetics and pharmacodynamics, and helps to predict the probability of target attainment and treatment outcome in patients. This article reviews the role of pharmacokinetic/pharmacodynamic approaches in the optimization of dosage regimens to maximize antibacterial efficacy while minimizing toxicity and emergence of resistance, and to achieve a high likelihood of therapeutic success. Polymyxin B, an approved drug with a narrow therapeutic window, serves as an illustrative example to highlight the importance of pharmacokinetic/pharmacodynamic modelling in conjunction with experimentation, employing static time-kill studies followed by dynamic in-vitro or in-vivo models, or both, to learn and confirm mechanistic insights necessary for translation to the bedside.

The goal of clinical research is to improve clinical practice. In progressive neurodegenerative conditions without any disease-slowing therapies, this will result in eventual approval of a first disease-modifying treatment. Clinical trials will still be needed to discover treatments that are more effective, safer, or more convenient. This will generate controversies over how to design these trials; specifically, controversies about the use of a placebo control. We consider ethical guidance for these studies with attention to 3 designs: placebo-controlled trials in the absence of the new drug, placebo-controlled trials with the approved drug as background therapy, and trials with the new drug as an active control. To understand the practical implications of these designs, we examine experiences in drug development in multiple sclerosis. We conclude by contemplating the future of clinical trials in Alzheimer disease.

Objectives: To determine the differences in information between prescribing guidelines and drug labeling, as well as to compare the approval of psychotropic medicines for major depression in pediatric patients ("pediatric depression") across countries. Methods: The recommendations of The Maudsley Prescribing Guidelines in Psychiatry (MPGP) for the treatment of pediatric depression (

Background Because of the highly heterogeneous nature of breast cancer, each subtype differs in response to several treatment regimens. This has limited the therapeutic options for metastatic breast cancer disease requiring exploration of diverse therapeutic models to target tumor specific biomarkers. Methods Differentially expressed breast cancer genes identified through extensive data mapping were studied for their interaction with other target proteins involved in breast cancer progression. The molecular mechanisms by which these signature genes are involved in breast cancer metastasis were also studied through pathway analysis. The potential drug targets for these genes were also identified. Results From 50 DEGs, 20 genes were identified based on fold change and p-value and the data curation of these genes helped in shortlisting 8 potential gene signatures that can be used as potential candidates for breast cancer. Their network and pathway analysis clarified the role of these genes in breast cancer and their interaction with other signaling pathways involved in the progression of disease metastasis. The miRNA targets identified through miRDB predictor provided potential miRNA targets for these genes that can be involved in breast cancer progression. Several FDA approved drug targets were identified for the signature genes easing the therapeutic options for breast cancer treatment. Conclusion The study provides a more clarified role of signature genes, their interaction with other genes as well as signaling pathways. The miRNA prediction and the potential drugs identified will aid in assessing the role of these targets in breast cancer.

Abstract: Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries (WHO, 2019), of which nearly two-third of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy (MDT), as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in last one-decade, and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli cannot grow in vitro. Besides, developing a new drug against leprosy through conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line (MDT) and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of “leprosy-free world”. This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

In February 2020, Italy was the first European country to detect coronavirus disease 2019 (COVID-19) in individuals and rapidly turned into one of the most-affected regions of the world. The National Health Service (NHS), which provides universal coverage to citizens, was challenged as never before in the history of the institution. Because no approved drug was available, patients received potentially effective drugs, participated in clinical trials, accessed compassionate drug use programs, or self-medicated.1 The aim of this study was to evaluate changes in drug demand during the early phase of the COVID-19 outbreak in Italy compared with the period before the outbreak.

The novel SARS-CoV-2 is a new disease that has caused severe destruction to human lives across the globe, including infection, mortality and financial crises, for which, scientific researchers have been directed towards the development of treatment and controlling measures against coronavirus. Currently, there has been no approved drug for the treatment of the disease, but several antiviral drugs have shown therapeutic effects from which, remdesivir and favipiravir are two such drugs. These drugs have shown some therapeutic potential in the treatment of COVID-19 by inhibiting viral enzyme RNA-dependent RNA polymerase. The purpose of this systematic review is to provide an overview of the effectiveness of these two drugs based on the clinical trials reported in current published data.

The fast spread of coronavirus 2019 (COVID-19) calls for immediate action to counter the associated significant loss of human life and deep economic impact. Certain patient populations like those with obesity and diabetes are at higher risk for acquiring severe COVID-19 disease and have a higher risk of COVID-19 associated mortality. In the absence of an effective and safe vaccine, the only immediate promising approach is to repurpose an existing approved drug. Several drugs have been proposed and tested as adjunctive therapy for COVID-19. Among these drugs are the glucagon-like peptide-1 (GLP-1) 2 agonists and the dipeptidylpeptidase-4 (DPP-4) inhibitors. Beyond their glucose-lowering effects, these drugs have several pleiotropic protective properties, which include cardioprotective effects, anti-inflammatory and immunomodulatory activities, antifibrotic effects, antithrombotic effects, and vascular endothelial protective properties. This narrative review discusses these protective properties and addresses their scientific plausibility for their potential use as adjunctive therapy for COVID-19 disease.

Introduction: Sacubitril-valsartan is a recently approved drug. However, there are few data regarding safety issues. We aimed to summarize the available evidence regarding sacubitril-valsartan’s safety and tolerability. Methods: We conducted a systematic review with meta-analysis of randomized controlled trials (RCTs) enrolling patients receiving sacubitril-valsartan for any condition, compared with standard therapy or placebo. Database search was performed in October 2019. Outcomes were adverse events (AEs), serious AEs (SAEs), discontinuation due to AEs, and five AEs of special interest. Data were reported using risk ratio (RR) and 95% confidence interval (95%CI). Results: We included 20 RCTs (22510 participants). When compared with active controls, there were no differences in SAEs (RR=0.93, 95%CI 0.86–1.01) and AEs (RR=1.00, 95%CI 0.97–1.03). However, sacubitril-valsartan resulted in an 8% risk reduction in discontinuation due to AEs (95%CI 0.85–0.99) and an increased risk of hypotension (RR=1.45, 95%CI 1.27–1.67). The risk of angioedema was higher with follow-ups greater than 12 months (RR=2.36, 95%CI 1.29–4.33). There were no further significant differences in the remaining AEs' risk. Conclusions: Sacubitril-valsartan was at least as safe and tolerable as active control, with a similar need of administration cautiousness, except for a higher risk of hypotension. However, one should consider the study’s limitations.

Many of the recently approved drug molecules that are therapeutically successful are found to be incompatible for the development of a novel delivery system and to take part in various health care management. Regardless of having better therapeutic properties, these molecules are barred from their effective clinical uses. The main reason attributed to it is poor solubility and/or poor permeability of drugs which finally emerges the drug to be low bioavailable. Nanoemulsions are one of the most acceptable nanolipoidal drug delivery system and appears to be a hope for the delivery of many of the Biopharmaceutical Classification System (BCS) class II and IV drugs. A nanoemulsion is a thermodynamically unstable isotropic mixture of oil, surfactant, and co-surfactants and is biphasic in nature. It can be either water in oil or oil in water and droplets are found in the range of 5 to 500 nm. The manufacturing and fabrication of nanoemulsions involve various natural, synthetic and semi synthetic materials using either low or high-energy methods. Application of nanoemulsions as a novel drug delivery system through several routes, especially oral, transdermal, ophthalmic, and intranasal, have been increased for various pharmacological aspects such as cardiovascular, anticancer, antimicrobial, and ophthalmic due to their stability, high solubilization capacity, and ease of preparation. The objective of this review is to focus on the aspects of manufacturing, fabrication, application, and some toxicological concerns related to nanoemulsions.

Randomized clinical trials are conducted to prove the efficacy of a new drug or more generally of a new pharmaceutical product. However, phase III-studies are usually not able to provide a full picture of the benefit-risk-profile of a new drug for several reasons which increases the likelihood that adverse drug reactions will occur after marketing approval that were not observed during phase III of clinical development. The knowledge gap regarding the benefit-risk-profile of a newly approved drug may be closed by pharmacoepidemiological studies based on large electronic healthcare databases after marketing approval. Databases increasingly represent an important worldwide data resource for pharmacoepidemiological research, but their information content, the covered timespan and the population size may heavily differ. In this chapter, we will provide an overview of existing databases worldwide that seem to be appropriate to conduct pharmacoepidemiological research. For this purpose, we will first briefly characterize and compare the major features of main types of databases and highlight their advantages and limitations in comparison to epidemiological field studies. We will then describe our search strategy to identify adequate databases for pharmacoepidemiological studies which are then presented in summary tables. We conclude with some remarks on necessary prerequisites for the successful use of existing databases.

Ocrelizumab is the first approved drug for primary progressive multiple sclerosis. Following appraisal by health technology assessment (HTA) bodies, this medicine has not been widely covered across European countries. We have compared the HTA process in England and France.We undertook an analysis of relevant documents that were published by the two HTA bodies. We analyzed patients' availability of Ocrelizumab at the different stages of the process.We identified differences in the assessment, one being the use of a different population of the pivotal trial, which has resulted in the consideration of distinct clinical effectiveness estimates. Ocrelizumab became available earlier in France as part of an early access program. However, rapid access was discontinued for newly eligible patients following an opinion concluding that Ocrelizumab yielded no additional benefit over placebo. This opinion was not compatible with the criteria allowing reimbursement in France.In England, there was no early access program and following an appraisal that included cost-effectiveness evaluation combined with pricing agreements, medicine was finally recommended. In conclusion, differences in the HTA process may result in appreciable differences in timing and outcome from marketing authorization to the adoption of newly licensed drugs.

Though already marketed antiviral drugs are used in the research to treat SARS CoV2 infection, the FDA approved drug and vaccine is still under different phases of clinical trials.

SARS-CoV2 is the coronavirus strain that causes acute respiratory syndromes or COVID19. It has been infecting around 33,000,000 people and causing 1.000,000 deaths around the world. SARS-CoV2 main protease plays a proteolytic role in producing viral polyproteins essential for virus replication. It is considered as an attractive therapeutic strategy. Drug repurposing approach by identifying and testing current available drugs that may bind and inhibit SARS-CoV2 main protease has been widely applied. Here, we computationally screened 2111 FDA (Food and Drug Administration)-approved drugs to investigate its potential interaction to the 3D crystal structure of SARS-CoV-2 main protease recently solved and deposited in Protein Data Bank (PDB). After virtual screening was performed to obtain the docking score and appropriate binding pose, the physic-based method using Molecular Mechanics combined with Generalized Born Surface Area (MM-GBSA) was further employed to estimate relative free binding energy of protease/drugs interaction (in kcal/mol). We report a list of six FDA-approved drugs that have similar and/or greater binding free energy than a peptidomimetic inhibitor of SARS-CoV2 main protease crystal structure used as a positive control. We observe the similarity of hydrogen bonding interactions with amino acids such as Glu166, Gly143, His164 that appear to stabilize the drug binding with protease providing valuable insights to be explored for further structure-activity relationship study and in vitro as well as in vivo validation.

Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

Alzheimer’s disease (AD) is regarded as one of the hallmark outcomes of an aging brain, and it is characterized by sequential loss of memory and changes in brain mass. In the advanced stage of the disease, a patient hardly recognizes the family members and fellow beings. Alzheimer’s disease represents one of the major contributors to the development of dementia, which is characterized by the formation of amyloid plaques and neurofibrillary tangles in brain tissues. In the recent past, several efforts pertaining to drug discovery have been made to interfere with the development and progression of Alzheimer’s disease. However, so far, no FDA approved drug is available to prevent or cure the disease. In recent days, generous attention is being given to formulating food-based therapeutic strategies to interfere with disease development and mitigate the symptoms. These food-based therapeutic formulations are loaded with critical bioactive compounds that provide specific health benefits in addition to supplementing fundamental nutrition. In the future, an amalgamation of modern knowledge of bioactive molecules with the traditional wisdom of food formulation will lead to the designing of a disease-specific therapeutic regime to prevent and cure numerous chronic diseases. Ayurveda, a herbal-based system of traditional medicines and therapeutic strategies, native to India and the Indian subcontinent, offers a number of unique strategies to prevent, delay, and cure various mental illnesses, including AD. It epitomizes the holistic method of treatment and promotes equilibrium in various dimensions of human existence and unification of the body, mind, and soul. There are several formulations that have claimed to slow down the age-related mental illnesses, and in general, enhance memory retention and improve cognitive behaviors. Some of the key bioactive molecules that serve as potential ingredients of nutraceuticals are obtained from native plants such as Turmeric (Curcuma longa), Tea (Camilla sinensis), Gingko (Ginkgo biloba), Cinnamon (Cinnamomum zeylanicum), Black pepper (Piper nigrum L.), Ginger (Zingiber officinale), etc. The efficiency and efficacy of these plants, which have been tested for the last 2000 years, show the richness of the ancient and ethnic Indian traditional knowledge. However, the effects of these preparations on biochemical processes of disease development at the molecular level are yet to be worked out. Nevertheless, in recent years, the needs for detailed pharmacological and toxicological studies have received the attention of researchers across the globe, and investigations are going on to substantiate the claimed pharmacological and therapeutic effects. This chapter will provide outlines of the current understanding of molecular mechanisms and hypotheses leading to the development of age-related mental illnesses and dementia in particular. It will also explore the existing therapeutic strategies, their limitations, and exploration of new possibilities, including the application of nutraceuticals, which in addition to providing basic nutrition signal, would also provide neuroprotective health benefits with minimum side effects.

Drug-induced liver injury (DILI) is one of the prevailing causes of fulminant hepatic failure. It is estimated that three idiosyncratic drug reactions out of four result in liver transplantation or death. Additionally, DILI is the most common reason for withdrawal of an approved drug from the market. Therefore, the development of methods for the early identification of hepatotoxic drug candidates is of crucial importance. This review focuses on the current state of cheminformatics strategies being applied for the early in silico prediction of DILI. Herein, we discuss key issues associated with DILI modeling in terms of the data size, imbalance and quality, complexity of mechanisms, and the different levels of hepatotoxicity to model going from general hepatotoxicity to the molecular initiating events of DILI.

It is clear from the analysis of the distribution of approved drug targets that enzymes continue to be a major target class for the pharmaceutical industry. The application of high-throughput screens designed to monitor the activity of these enzyme targets, and the ability of test compounds to modulate this activity, is still the predominant hit finding approach in the industry. The widespread use of enzyme activity-based screens has led to the development of several useful guidelines for the development and validation of robust and reliable assays. Key learnings for the development, validation, and implementation of acoustic mist ionization mass spectrometry for high-throughput enzyme assays are described.

We present a Chemistry and Structure Screen Integrated Efficiently (CASSIE) approach (named for Greek prophet Cassandra) to design inhibitors for cancer biology and pathogenesis. CASSIE provides an effective path to target master keys to control the repair-replication interface for cancer cells and SARS CoV-2 pathogenesis as exemplified here by specific targeting of Poly(ADP-ribose) glycohydrolase (PARG) and ADP-ribose glycohydrolase ARH3 macrodomains plus SARS CoV-2 nonstructural protein 3 (Nsp3) Macrodomain 1 (Mac1) and Nsp15 nuclease. As opposed to the classical massive effort employing libraries with large numbers of compounds against single proteins, we make inhibitor design for multiple targets efficient. Our compact, chemically diverse, 5000 compound Goldilocks (GL) library has an intermediate number of compounds sized between fragments and drugs with predicted favorable ADME (absorption, distribution, metabolism, and excretion) and toxicological profiles. Amalgamating our core GL library with an approved drug (AD) library, we employ a combined GLAD library virtual screen, enabling an effective and efficient design cycle of ranked computer docking, top hit biophysical and cell validations, and defined bound structures using human proteins or their avatars. As new drug design is increasingly pathway directed as well as molecular and mechanism based, our CASSIE approach facilitates testing multiple related targets by efficiently turning a set of interacting drug discovery problems into a tractable medicinal chemistry engineering problem of optimizing affinity and ADME properties based upon early co-crystal structures. Optimization efforts are made efficient by a computationally-focused iterative chemistry and structure screen. Thus, we herein describe and apply CASSIE to define prototypic, specific inhibitors for PARG vs distinct inhibitors for the related macrodomains of ARH3 and SARS CoV-2 Nsp3 plus the SARS CoV-2 Nsp15 RNA nuclease.

Despite COVID-19 turned into a pandemic, no approved drug for the treatment or globally available vaccine is out yet. In such a global emergency, drug repurposing approach that bypasses a costly and long-time demanding drug discovery process is an effective way in search of finding drugs for the COVID-19 treatment. Recent studies showed that SARS-CoV-2 uses neuropilin-1 (NRP1) for host entry. Here we took advantage of structural information of the NRP1 in complex with C-terminal of spike (S) protein of SARSCoV-2 to identify drugs that may inhibit NRP1 and S protein interaction. U.S. Food and Drug Administration (FDA) approved drugs were screened using docking simulations. Among top drugs, well-tolerated drugs were selected for further analysis. Molecular dynamics (MD) simulations of drugs-NRP1 complexes were run for 100 ns to assess the persistency of binding. MM/GBSA calculations from MD simulations showed that eltrombopag, glimepiride, sitagliptin, dutasteride, and ergotamine stably and strongly bind to NRP1. In silico Alanine scanning analysis revealed that Tyr(297), Trp(301), and Tyr(353) amino acids of NRP1 are critical for drug binding. Validating the effect of drugs analyzed in this paper by experimental studies and clinical trials will expedite the drug discovery process for COVID-19., NA

SUMMARYChimeric antigen receptor (CAR) T cell immunotherapy has the potential to revolutionize cancer medicine. However, excessive CAR activation, lack of tumor-specific surface markers, and antigen escape have limited the safety and efficacy of CAR T cell therapy. A multi-antigen targeting CAR system that is regulated by safe, clinically-approved pharmaceutical agents is urgently needed, yet only a few simple systems have been developed, and even fewer have been evaluated for efficacy in vivo. Here, we present NASCAR (NS3 ASsociated CAR), a collection of induc-ible ON and OFF switch CAR circuits engineered with a NS3 protease domain deriving from the Hepatitis C Virus (HCV). We establish their ability to regulate CAR activity using multiple FDA-approved antiviral protease inhibitors, including grazoprevir (GZV), both in vitro and in a xenograft tumor model. In addition, we have engineered several dual-gated NASCAR circuits, consisting of an AND logic gate CAR, universal ON-OFF CAR, and a switchboard CAR. These engineered receptors enhance control over T cell activity and tumor-targeting specificity. Together, our com-prehensive set of multiplex drug-gated CAR circuits represent a dynamic, tunable, and clinically-ready set of modules for enhancing the safety of CAR T cell therapy.

The most iconic word of the year 2020 is 'COVID-19', the shortened name for coronavirus disease 2019. The pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is responsible for multiple worldwide lockdowns, an economic crisis, and a substantial increase in hospitalizations for viral pneumonia along with respiratory failure and multiorgan dysfunctions. Recently, the first few vaccines were approved by World Health Organization (WHO) and can eventually save millions of lives. Even though, few emergency use drugs like Remdesivir and several other repurposed drugs, still there is no approved drug for COVID-19. The coronaviral encoded proteins involved in host-cell entry, replication, and host-cell invading mechanism are potentially therapeutic targets. This perspective review provides the molecular overview of SARS-CoV-2 life cycle for summarizing potential drug targets, structural insights, active site contour map analyses of those selected SARS-CoV-2 protein targets for drug discovery, immunology, and pathogenesis.

Hyperlipidemia causes diseases like cardiovascular disease, cancer, Type II Diabetes and Alzheimer's disease. Drugs that specifically target HL associated diseases are required for treatment. 34 KEGG pathways targeted by lipid lowering drugs were used to construct a directed protein-protein interaction network and driver nodes were determined using CytoCtrlAnalyser plugin of Cytoscape 3.6. The involvement of driver nodes of HL in other diseases was verified using GWAS. The central nodes of the network and 34 overrepresented pathways had a critical role in Hyperlipidemia. The PI3K-AKT signalling pathway, non-essentiality, non-centrality and approved drug target status were the predominant features of the driver nodes. Next, a Random Forest classifier was trained on 1445 molecular descriptors calculated using PaDEL for 50 approved lipid lowering and 84 lipid raising drugs as the positive and negative training set respectively. The classifier showed average accuracy of 76.8 % during 5-fold cross validation with AUC of 0.79 ± 0.06 for the ROC curve. The classifier was applied to select molecules with favourable properties for lipid lowering from the 130 approved drugs interacting with the identified driver nodes. We have integrated diverse network data and machine learning to predict repurposing of nine drugs for treatment of HL associated diseases.

The progressive and fatal outbreak of the newly emerged coronavirus, SARS-CoV-2, necessitates rigorous collaboration of all health care systems and researchers from all around the world to bring such a devastating pandemic under control. As there is so far no officially approved drug or ideal vaccine for this disease, investigations on this infectious disease are actively pursued. Chitin and chitosan have shown promising results against viral infections. In this review, we first delve into the problematic consequences of viral pandemics followed by an introduction on SARS-CoV-2 taxonomical classification. Then, we elaborate on the immunology of COVID-19. Common antiviral therapies and their related limitations are described and finally, the potential applicability of chitin and chitosan to fight this overwhelming viral pandemic is addressed.

COVID-19 has rapidly spread worldwide and incidences of hospitalisation from respiratory distress are significant. While a vaccine is in the pipeline, there is urgency for therapeutic options to address the immune dysregulation, hyperinflammation and oxidative stress that can lead to death. Given the shared pathogenesis of severe cases of COVID-19 with aspects of multiple sclerosis and psoriasis, we propose dimethyl fumarate as a viable treatment option. Currently approved for multiple sclerosis and psoriasis, dimethyl fumarate is an immunomodulatory, anti-inflammatory and anti-oxidative drug that could be rapidly implemented into the clinic to calm the cytokine storm which drives severe COVID-19.

International audience; With the spread of drug resistance, new antimicrobials are urgently needed. Here, we set out to tackle this problem by high-throughput exploration for novel antifungal synergies among combinations of approved, nonantifungal drugs; a novel strategy exploiting the potential of alternative targets, low chemicals usage and low development risk. We screened the fungal pathogen Candida albicans by combining a small panel of nonantifungal drugs (all in current use for other clinical applications) with 1280 compounds from an approved drug library. Screens at sublethal concentrations of the antibiotic paromomycin (PM), the antimalarial primaquine (PQ), or the anti-inflammatory drug ibuprofen (IF) revealed a total of 17 potential strong, synergistic interactions with the library compounds. Susceptibility testing with the most promising combinations corroborated marked synergies [fractional inhibitory concentration (FIC) indices ≤0.5] between PM + β-escin, PQ + celecoxib, and IF + pentamidine, reducing the MICs of PM, PQ, and IF in C. albicans by >64-, 16-, and 8-fold, respectively. Paromomycin + β-escin and PQ + celecoxib were effective also against C. albicans biofilms, azole-resistant clinical isolates, and other fungal pathogens. Actions were specific, as no synergistic effect was observed in mammalian cells. Mode of action was investigated for one of the combinations, revealing that PM + β-escin synergistically increase the error-rate of mRNA translation and suggesting a different molecular target to current antifungals. The study unveils the potential of the described combinatorial strategy in enabling acceleration of drug-repurposing discovery for combatting fungal pathogens.

Angiotensin-converting enzyme 2 (ACE2) is a membrane-bound zinc metallopeptidase that generates the vasodilatory peptide angiotensin 1–7 and thus performs a protective role in heart disease. It is considered an important therapeutic target in controlling the COVID-19 outbreak, since SARS-CoV-2 enters permissive cells via an ACE2-mediated mechanism. The present in silico study attempted to repurpose existing drugs for use as prospective viral-entry inhibitors targeting human ACE2. Initially, a clinically approved drug library of 7,173 ligands was screened against the receptor using molecular docking, followed by energy minimization and rescoring of docked ligands. Finally, potential binders were inspected to ensure molecules with different scaffolds were engaged in favorable contacts with both the metal cofactor and the critical residues lining the receptor’s active site. The results of the calculations suggest that lividomycin, burixafor, quisinostat, fluprofylline, pemetrexed, spirofylline, edotecarin, and diniprofylline emerge as promising repositionable drug candidates for stabilizing the closed (substrate/inhibitor-bound) conformation of ACE2, thereby shifting the relative positions of the receptor’s critical exterior residues recognized by SARS-CoV-2. This study is among the rare ones in the relevant scientific literature to search for potential ACE2 inhibitors. In practical terms, the drugs, unmodified as they are, may be introduced into the therapeutic armamentarium of the ongoing fight against COVID-19 now, or their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors in the near future., Graphical abstract Image 1, Highlights • A drug library of 7173 ligands was screened against ACE2 using molecular docking. • The predicted ACE2–ligand complexes were optimized via molecular mechanics. • On closer examination, eight promising repositionable drug candidates were proposed. • The drugs, unmodified as they are, may serve as entry inhibitors of SARS-CoV-2. • Their scaffolds may serve as rich skeletons for designing novel ACE2 inhibitors.

The global pandemic COVID-19, caused by novel coronavirus SARS-CoV-2, has emerged as severe public health issue crippling world health care systems. Substantial knowledge has been generated about the pathophysiology of the disease and possible treatment modalities in a relatively short span of time. As of August 19, 2020, there is no approved drug for the treatment of COVID-19. More than 600 clinical trials for potential therapeutics are underway and the results are expected soon. Based on early experience, different treatment such as anti-viral drugs (remdesivir, favipiravir, lopinavir/ritonavir), corticosteroids (methylprednisolone, dexamethasone) or convalescent plasma therapy are recommended in addition to supportive care and symptomatic therapy. There are several treatments currently being investigated to address the pathological conditions associated with COVID-19. This review provides currently available information and insight into pathophysiology of the disease, potential targets, and relevant clinical trials for COVID-19.

Background COVID-19 is a global public health crisis with no effective therapeutic strategies or vaccines available. The disease is caused by the SARS-CoV-2 virus, a novel coronavirus that enters cells through the ACE2 receptor. To rapidly identify existing drugs that might preferentially bind to the ACE2 receptor we sought to use an artificial intelligence platform to evaluate ~3,000 known drugs in the FDA approved drug library (Selleckchem). Methods Fluency is a quantitative structure–activity relationship (QSAR) deep learning-based platform that evaluates small molecule drug binding to protein targets. All drug structures from the FDA approved library were evaluated for binding to the ACE2 receptor and re-filtered for preferential ACE2 vs. ACE1 receptor binding. Top hits were evaluated for specificity by predicting binding across the human proteome and filtered by evaluating rankings from each of two models along with average ranks and combined scores from both models. The drugs were then evaluated for classification, potential availability and prioritized for in vitro validation. Selected compounds were screened using a high-throughput SARS-CoV-2 cell-based assay as described previously (Jonsson et al. J Biomol Screen 2007 12: 33. DOI: 10.1177/1087057106296688). Plates are quality-controlled in each run using Z score and CV statistics. Positive controls consisting of cells only and negative controls consisting of virus were used to normalize the data. Individual drugs are added to each plate at a single dose with at least four doses tested. For titer reduction assays, VeroE6 cells are infected with virus at MOI of 0.1 for one hour to promote adsorption. After two days, the supernatant is harvested and the amount of virus in each well is measured using TCID50 or plaque assay. Results We identified 25 top drugs that were predicted to bind to ACE2 receptors and could theoretically block SARS-CoV-2 cell entry. Of these drugs, we prioritized 12 drugs for validation covering multiple pharmacologic classes and after assessing drug availability (table 1). They included an ALK/EGFR inhibitor, JAK inhibitor, two electrolyte channel inhibitors, \an antibiotic, and several anti-viral drugs, ACE inhibitors and anticoagulants. Validation studies are in progress and viral inhibition and titer reduction data will be presented. Conclusions Our data show that machine learning platforms can be used to rapidly identify existing drugs that may have activity against SARS-CoV-2 infection. This hybrid computational and experimental approach enables rapid discovery of drugs for clinical testing against COVID-19 and other emerging human diseases. Acknowledgements We would like to thank Dr. Colleen Jonsson and Dr. Jeremy Smith at Oak Ridge National Laboratories and the University of Tennessee Regional Biocontainment Laboratory for assistance with in vitro validation studies. Trial Registration N/A Ethics Approval N/A Consent N.A

The ongoing pandemic of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health. Drug repurposing is a time-efficient approach to finding effective drugs against SARS-CoV-2 in this emergency. Here, we present a robust experimental design combining deep learning with molecular docking experiments to identify the most promising candidates from the list of FDA-approved drugs that can be repurposed to treat COVID-19. We have employed a deep learning-based Drug Target Interaction (DTI) model, called DeepDTA, with few improvements to predict drug-protein binding affinities, represented as KIBA scores, for 2440 FDA-approved and 8168 investigational drugs against 24 SARS-CoV-2 viral proteins. FDA-approved drugs with the highest KIBA scores were selected for molecular docking simulations. We ran around 50,000 docking simulations for 168 selected drugs against 285 total predicted and/or experimentally proven active sites of all 24 SARS-CoV-2 viral proteins. A list of 49 most promising FDA-approved drugs with the best consensus KIBA scores and binding affinity values against selected SARS-CoV-2 viral proteins was generated. Most importantly, 16 drugs including anidulafungin, velpatasvir, glecaprevir, rifapentine, flavin adenine dinucleotide (FAD), terlipressin, and selinexor demonstrated the highest predicted inhibitory potential against key SARS-CoV-2 viral proteins. We further measured the inhibitory activity of 5 compounds (rifapentine, velpatasvir, glecaprevir, anidulafungin, and FAD disodium) on SARS-CoV-2 PLpro using Ubiquitin-Rhodamine 110 Gly fluorescent intensity assay. The highest inhibition of PLpro activity was seen with rifapentine (IC50: 15.18 μM) and FAD disodium (IC50: 12.39 μM), the drugs with high predicted KIBA scores and binding affinities., Graphical abstract Image 1

One of the defining moments of the 80-year evolution of menopausal hormone therapy (MHT) was the 2002 reveal of the initial results of the combined hormone therapy arm of the Women's Health Initiative (WHI) clinical trial. The exodus from regulatory approved MHT was prompt and profound and accompanied by a rapid acceleration of the compounding pharmacy 'bioidentical' hormone therapy industry. Compounders had recruited prescribers and promoted compounded bioidentical hormone therapy (cBHT) well before the WHI, yet the startling results provided a catalyst that enabled a leap in production of compounded hormones that were variably regulated, basically unstudied, and inconsistently labeled. In this review, the story of the rise of cBHT and the regulatory double standard is eclipsed only by the 2020 findings and recommendations of the US National Academies of Science, Engineering, and Medicine. Their investigation, commissioned by the US Food and Drug Administration, was tasked to: provide an evidence-based summary of the clinical utility of cBHT; evaluate whether the evidence of safety and efficacy supports the use of cBHT; and identify patient populations that might need cBHT in lieu of an approved drug product. Their conclusions are consistent with sound science and their recommendations are in harmony with global menopause societies.

Coronavirus infectious diseases 2019 (COVID-19), a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been a serious public health threat worldwide. So far, there are no drugs and vaccines whose efficacy has been well-proven. After the outbreak, there has been a massive search for anti-SARS-CoV-2 medications, focusing on approved drugs because repurposing approved drugs will take less time to reach clinical usage than new drugs. This article summarizes the studies using in silico and in vitro approaches to identify therapeutic candidates among approved drugs that target the SARS-CoV-2 life cycle., Highlights • Approved drugs are screened to identify anti-SARS-CoV-2 candidates. • Screening approved drugs enables faster identification at low costs. • Some of the identified drugs are under clinical evaluation. • In silico, in vitro, cell culture, and in vivo approaches have been used. • There needs to be a more in-depth analysis of drug mechanisms against SARS-CoV-2.

To clarify the approval status of molecular targeted antineoplastic drugs in the United States (U.S.), the European Union (E.U.), and Japan (JP), we checked the status of pediatric indications according to the package insert of each drug. A total of 103 drugs were approved for adult patients in at least one of the three regions whereas only 19 drugs were approved for pediatric patients. Sixty-six of 103 drugs (64.1%) had adult indications in the U.S., the E.U., and JP, whereas only three drugs had pediatric indications in all three regions. Abnormalities in six genes (NRAS, ABL1, JAK2, KIT, ALK and BRAF) were common in childhood cancers as well as adult cancers, for which at least one approved drug could be a potentially actionable drug. Although there were 16 candidate drugs that had adult indications for these abnormalities, only three drugs (18.8%) had pediatric indications. We confirmed that there were few molecular targeted antineoplastic drugs with pediatric indications in the U.S., the E.U., and JP compared with the number of approved drugs for adults. Drugs targeting genomic abnormalities which were common in both adult and pediatric cancers were considered to be good candidates for expansion of their indication for pediatric patients.

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., Graphical abstract Unlabelled Image

BackgroundDengue is a serious public health concern worldwide, with ~3 billion people at risk of contracting dengue virus (DENV) infections. Currently, no effective vaccine or drug is available for the prevention or treatment of dengue, which leaves only anti-mosquito strategies to combat this disease. The present study was initiated to determine the in-vitro and in vivo protective effects of a plant-derived phytopharmaceutical drug for the treatment of dengue.Methodology/Principal FindingsIn our previous report, we had identified methanolic extract of the aerial parts of Cissampelos pareira to exhibit in vitro and in vivo anti-dengue activity against all the four DENV serotypes. In the current study, we have identified another Indian medicinal plant, Cocculus hirsutus, which has a more potent anti-dengue activity than C. pareira. The activity has been evaluated through flow-cytometry-based virus inhibition assay. Interestingly, the stem of C. hirsutus was found to be more potent than the aerial part irrespective of the extraction solvent used viz., denatured spirit, hydro-alcohol (50:50) and water. Hence, the aqueous extract of stem of C. hirsutus (AQCH) was further advanced for investigations because of greater regulatory acceptance. The AQCH exhibited dose-dependent inhibition of release of DENV and its secretory antigen, NS1. Five chemical markers viz. Sinococuline, 20-Hydroxyecdysone, Makisterone-A, Magnoflorine and Coniferyl alcohol were identified as the major chemical ingredients of the AQCH extract. These chemicals were subsequently used for extract standardisation. Importantly, AQCH completely protected AG129 mice at 25 mg/kg/dose body weight when fed 4 times a day post-infection with a lethal dose of DENV-2 S221 strain. Because of its potential as an effective phytopharmaceutical drug against dengue, AQCH, has been formulated into tablets for further pre-clinical and clinical developments.Conclusions/SignificanceWe provide evidence of the pan anti-dengue potential of C. hirsutus-based phytopharmaceutical drug as determined through in vitro and in vivo experiments. We have also characterized five chemical entities in the drug substance, which provides means for standardization of drug substance and drug product. Based on these findings, a program to develop a safe and effective C. hirsutus-derived phytopharmaceutical drug for the treatment of dengue has been initiated.Author summaryThere is an urgent need to develop a safe and effective drug against dengue, which is a rapidly expanding mosquito-borne viral disease. Half of the world’s population has been estimated to be at risk of contracting this disease and the situation remains grim due to lack of an approved drug. We aimed to develop an ethnopharmacological drug against dengue by exploring traditional Indian medicinal science, Ayurveda. This led us to identify a creeper, Cocculus hirsutus, as a more potent anti-dengue plant than Cissampelos pareira, reported in our earlier published study. The stem part of C. hirsutus was found to be more efficacious in inhibiting the propagation of dengue viruses (DENVs) in cell culture than its aerial part. Hence, we chose to advance aqueous extract of stem of C. hirsutus (AQCH) for further studies. Importantly, AQCH also protected immune-compromised mice from lethal DENV infection, which is suggestive of its potential clinical relevance. We have identified five chemical marker compounds in AQCH to gauge the quality and consistency of extract preparation and its formulation into stable tablets. Based on the findings of this study, we have undertaken the development of a safe and effective C. hirsutus-derived phytopharmaceutical drug for the treatment of dengue.

Despite the frightening mortality rate associated with COVID-19, there is no known approved drug to effectively combat the pandemic. COVID-19 clinical manifestations include fever, fatigue, cough, shortness of breath, and other complications. At present, there is no known effective treatment or vaccine that can mitigate/inhibit SARS-CoV-2. Available clinical intervention for COVID-19 is only palliative and limited to support. Thus, there is an exigent need for effective and non-invasive treatment. This article evaluates the possible mechanism of actions of SARS-CoV-2 and present Nigeria based medicinal plants which have pharmacological and biological activities that can mitigate the hallmarks of the pathogenesis of COVID-19. SARS-CoV-2 mode of actions includes hyper-inflammation characterized by a severe and fatal hyper-cytokinaemia with multi-organ failure; immunosuppression; reduction of angiotensin-converting enzyme 2 (ACE2) to enhance pulmonary vascular permeability causing damage to the alveoli; and further activated by open reading frame (ORF)3a, ORF3b, and ORF7a via c-Jun N- terminal kinase (JNK) pathway which induces lung damage. These mechanisms of action of SARS-CoV-2 can be mitigated by a combination therapy of medicinal herbs based on their pharmacological activities. Since the clinical manifestations of COVID-19 are multifactorial with co-morbidities, we strongly recommend the use of combined therapy such that two or more herbs with specific therapeutic actions are administered to combat the mediators of the disease., SARS-CoV-2; Antivirals; COVID-19; Phytochemicals; Coronavirus; Medicinal plants; Biochemistry; Epidemiology; Food science; Health sciences; Pathophysiology; Toxicology; Phytochemistry; Evidence based medicine.

Background and Aims Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) induced Novel Coronavirus Disease (COVID-19) has currently become pandemic worldwide. Though drugs like remdesivir, favipiravir, and dexamethasone found beneficial for COVID-19 management, they have limitations clinically, and vaccine development takes a long time. The researchers have reported key proteins which could act as druggable targets. Among them, the major protease Mpro is first published, plays a prominent role in viral replication and an attractive drug-target for drug discovery. Hence, to target Mpro and inhibit it, we accomplished the virtual screening of US-FDA approved drugs using well-known drug repurposing approach by computer-aided tools. Methods The protein Mpro, PDB-ID 6LU7 was imported to Maestro graphical user interphase of Schrödinger software. The US-FDA approved drug structures are imported from DrugBank and docked after preliminary protein and ligand preparation. The drugs are shortlisted based on the docking scores in the Standard Precision method (SP-docking) and then based on the type of molecular interactions they are studied for molecular dynamics simulations. Results The docking and molecular interactions studies, five drugs emerged as potential hits by forming hydrophilic, hydrophobic, electrostatic interactions. The drugs such as arbutin, terbutaline, barnidipine, tipiracil and aprepitant identified as potential hits. Among the drugs, tipiracil and aprepitant interacted with the Mpro consistently, and they turned out to be most promising. Conclusions This study shows the possible exploration for drug repurposing using computer-aided docking tools and the potential roles of tipiracil and aprepitant, which can be explored further in the treatment of COVID-19., Graphical abstract

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity.

As biologic based drugs become an increasingly important sector of the pharmaceutical industry, accurate and precision techniques for bioanalysis are required to support clinical trials and beyond. Ranibizumab, a fab therapeutic, is an FDA approved drug to treat wet age-related macular degeneration (AMD), as well as other eye related diseases. Ranibizumab’s mAb counterpart, bevacizumab, is often also used off-label to treat wet AMD. Ranibizumab and bevacizumab target circulating VEGF-A in the eye, reducing unwanted angiogenesis. Since these drugs are designed for local intravitreal administration, concentration levels in human plasma are expected to be significantly lower compared to vitreous fluid concentrations, presenting bioanalytical challenges. However, this is important for assessment of drug toxicity. In this manuscript, we describe the development, optimization, and validation of an LC-MS/MS method designed for quantitative bioanalysis of ranibizumab and bevacizumab in human plasma following intravitreal administration. In order to fully develop this method, evaluations were conducted to optimize the conditions, including selection of the surrogate peptide by in-silico experiments, optimizations of the immunocapture, denaturation, reduction, alkylation, and digestion extraction steps, as well as optimization of the LC-MS/MS conditions, and evaluation of a dissociation step to determine if there was interference from VEGF or ADAs. Once the method was fully optimized, it was then validated, following the 2018 FDA guidance on bioanalytical method validations. This method is now available for use during clinical trials and precision medicine, for the quantitative evaluation of systemic exposure of ranibizumab or bevacizumab in human plasma after intravitreal administration, with a linear calibration range of 0.300–100 ng/mL.

The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research 2020, 178, 104787) show a potent inhibition of SARS-CoV-2 replication in vitro by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CLpro and PLpro, and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host- and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.

To discover effective drugs for COVID-19 treatment amongst already clinically approved drugs, we developed a high throughput screening assay for SARS-CoV-2 virus entry inhibitors using SARS2-S pseudotyped virus. An approved drug library of 1800 small molecular drugs was screened for SARS2 entry inhibitors and 15 active drugs were identified as specific SARS2-S pseudovirus entry inhibitors. Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that 7 of these drugs (clemastine, amiodarone, trimeprazine, bosutinib, toremifene, flupenthixol, and azelastine) significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity. Three of the drugs were classified as histamine receptor antagonists with clemastine showing the strongest anti-SARS2 activity (EC50 = 0.95 ± 0.83 µM). Our work suggests that these 7 drugs could enter into further in vivo studies and clinical investigations for COVID-19 treatment.

Hepatocellular carcinoma (HCC) is the primary liver cancer that has shown a high incidence and mortality rate worldwide among several types of cancers. A large variety of chemotherapeutic agents employed for the treatment have a limited success rate owing to their limited site-specific drug targeting ability. Thus, there is a demand to develop novel approaches for the treatment of HCC. With advancements in nanotechnology-based drug delivery approaches, the challenges of conventional chemotherapy have been continuously decreasing. Nanomedicines constituted of lipidic and polymeric composites provide a better platform for delivering and opening new pathways for HCC treatment. A score of nanocarriers such as surface-engineered liposomes, nanoparticles, nanotubes, micelles, quantum dots, etc., has been investigated in the treatment of HCC. These nanocarriers are considered to be highly effective clinically for delivering chemotherapeutic drugs with high site-specificity ability and therapeutic efficiency. The present review highlights the current focus on the application of nanocarrier systems using various ligand-based receptor-specific targeting strategies for the treatment and management of HCC. Moreover, the article has also included information on the current clinically approved drug therapy for hepatocellular carcinoma treatment and updates of regulatory requirements for approval of such nanomedicines.

International audience; The 1,3-benzothiazole (BTZ) ring may offer a valid option for scaffold-hopping from indole derivatives. Several BTZs have clinically relevant roles, mainly as CNS medicines and diagnostic agents, with riluzole being one of the most famous examples. Riluzole is currently the only approved drug to treat amyotrophic lateral sclerosis (ALS) but its efficacy is marginal. Several clinical studies have demonstrated only limited improvements in survival, without benefits to motor function in patients with ALS. Despite significant clinical trial efforts to understand the genetic, epigenetic, and molecular pathways linked to ALS pathophysiology, therapeutic translation has remained disappointingly slow, probably due to the complexity and the heterogeneity of this disease. Many other drugs to tackle ALS have been tested for 20 years without any success. Dexpramipexole is a BTZ structural analog of riluzole and was a great hope for the treatment of ALS. In this review, as an interesting case study in the development of a new medicine to treat ALS, we present the strategy of the development of dexpramipexole, which was one of the most promising drugs against ALS.

COVID-19, the disease caused by SARS-CoV-2 (1), was declared a pandemic by the World Health Organization (WHO) in March 2020 (2). While awaiting a vaccine, several antivirals are being used to manage the disease with limited success (3, 4). To expand this arsenal, we screened 4 compound libraries: a United States Food and Drug Administration (FDA) approved drug library, an angiotensin converting enzyme-2 (ACE2) targeted compound library, a flavonoid compound library as well as a natural product library. Of the 121 compounds identified with activity against SARS-CoV-2, 7 were shortlisted for validation. We show for the first time that the active form of Vitamin D, calcitriol, exhibits significant potent activity against SARS-CoV-2. This finding paves the way for consideration of host-directed therapies for ring prophylaxis of contacts of SARS-CoV-2 patients.

The World Health Organization (WHO) declared COVID -19 a pandemic on March 11, since then, scientists have been working tirelessly to develop drugs and vaccines against it. Unfortunately, yet there is no approved drug or vaccine available for the treatment of the virus. More so, developing effective antiviral and vaccine against COVID 19 remains a major challenge. However, numerous NPs is known to have possessed an inherit antiviral effect and they have been utilized as a promising carrier for effective targeted delivery with low side effect/adverse effect. Perhaps, exploring the concept of nanotechnology in battling COVID 19 will ensure an excellent therapeutic prognosis. The review focus on emphasizing the need to explore the concept of nanotechnology as a gold possibility that could potentiate the world to win the fight against COVID -19.

The novel human coronavirus-2 (HCoV-2), called SARS-CoV-2, is the causative agent of Coronavirus Induced Disease (COVID-19) and has spread causing a global pandemic. Currently, there is no vaccine to prevent infection nor any approved drug for the treatment. The development of a new drug is time-consuming and cannot be relied on as a solution in combatting the immediate global challenge. In such a situation, the drug repurposing becomes an attractive solution to identify the potential of COVID-19 treatment by existing drugs, which are approved for other indications. Here, we review the potential use of rapamycin, an mTOR (Mammalian Target of Rapamycin) inhibitor that can be repurposed at low dosages for the treatment of COVID-19. Rapamycin inhibits protein synthesis, delays aging, reduces obesity in animal models, and inhibits activities or expression of pro-inflammatory cytokines such as IL-2, IL-6 and, IL-10. Overall, the use of rapamycin can help to control viral particle synthesis, cytokine storms and contributes to fight the disease by its anti-aging and anti-obesity effects. Since, rapamycin targets the host factors and not viral machinery, it represents a potent candidate for the treatment of COVID-19 than antiviral drugs as its efficacy is less likely to be dampened with high mutation rate of viral RNA. Additionally, the inhibitory effect of rapamycin on cell proliferation may aid in reducing viral replication. Therefore, by drug repurposing, low dosages of rapamycin can be tested for the potential treatment of COVID-19/SARS-CoV-2 infection., Graphical abstract Image 1, Highlights • Rapamycin, an mTOR inhibitor can be repurposed for treatment of COVID-19. • Rapamycin inhibits protein synthesis, pro-inflammatory cytokines and delays aging. • Rapamycin action targeted on host factors and not viral machinery. • Rapamycin act on cell proliferation may aid in reducing viral replication.

MKK7 (MEK7) is a key regulator of the JNK stress signaling pathway and targeting MKK7 has been proposed as a chemotherapeutic strategy. Detailed understanding of the MKK7 structure and factors that impact its activity is therefore of critical importance. Here, we present a comprehensive set of MKK7 crystal structures revealing insights into catalytic domain plasticity and the role of the N-terminal regulatory helix, conserved in all MAP2Ks, mediating kinase activation. Crystal structures harboring this regulatory helix revealed typical structural features of active kinase, providing exclusively a first model of the MAP2K active state. A small molecule screening campaign yielded multiple scaffolds, including type-II irreversible inhibitors a binding mode that has not been reported previously. We also observed an unprecedented allosteric pocket located in the N-terminal lobe for the approved drug ibrutinib. Collectively, our structural and functional data expand and provide alternative targeting strategies for this important MAP2K kinase.

The National Center for Advancing Translational Sciences (NCATS) has developed an online open science data portal for its COVID-19 drug repurposing campaign – named OpenData – with the goal of making data across a range of SARS-CoV-2 related assays available in real-time. The assays developed cover a wide spectrum of the SARS-CoV-2 life cycle, including both viral and human (host) targets. In total, over 10,000 compounds are being tested in full concentration-response ranges from across multiple annotated small molecule libraries, including approved drug, repurposing candidates and experimental therapeutics designed to modulate a wide range of cellular targets. The goal is to support research scientists, clinical investigators and public health officials through open data sharing and analysis tools to expedite the development of SARS-CoV-2 interventions, and to prioritize promising compounds and repurposed drugs for further development in treating COVID-19.

SARS-CoV-2 is a novel RNA coronavirus responsible of a deadly pandemic: the clinical illness COVID-19. With only one authorized drug for emergency use in critically ill patients: Remdesivir, there is not any other approved drug or vaccine yet with proven potential to overcome this infection. We exposed here many scientific evidences to support our novel idea that a macrolide, basically Clarithromycin, could be effective as a single agent for treatment and prophylaxis of COVID-19. Clarithromycin could change the history of this pandemic. It could reduce the costs of treatment and the potential adverse effects when combining more than one drug such as with Hydroxychloroquine. Clarithromycin treatment and prophylaxis as a single agent could be much more simple, safe and cheaper as giving Chloroquine or Hydroxychloroquine alone or in combination with Azithromycin as well as other therapeutic options. Fil: Mansilla, Eduardo. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: Martínez, Ricardo Rangel. ExomePharma; México Fil: Marin, Gustavo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Médicas; Argentina Fil: Filho, Idiberto Zotarelli. Faceres Medical School; Brasil Fil: Rivas, Elsa. Hospital de la Amistad Perú - Corea San Rosa II; Perú Fil: Rivas, Jaime. Hospital de la Amistad Perú - Corea San Rosa II; Perú Fil: Carvalho, Katherine Athayde Teixeira de. Research Institute Pelé Little Prince; Brasil Fil: Dayer, Mohammad Reza. Shahid Chamran University of Ahvaz; Irán Fil: Samadikuchaksaraei, Alí. Iran University of Medical Sciences; Irán