Immunopharmacol Immunotoxicol. 2022 Sep 26:1-33. doi: 10.1080/08923973.2022.2128370. Online ahead of print.

ABSTRACT

The level of precursors involved in the biosynthesis of glycosaminoglycan (GAG), glucosamine synthase, and N-acetyl glucosamine (NAG), are significantly reduced in inflammatory bowel disease (IBD). This results in deficient GAG content in mucosa, which eventually disrupts the gut wall integrity, provoking abnormal immunological responses. This is characterized by colossal liberation of inflammatory mediators including tumor necrosis factor-alpha (TNF-α), interleukins (IL), and reactive oxygen species provoking colonic inflammation. D-glucosamine (D-GLU) is reported to suppress oxidative stress, and pro-inflammatory cytokines and acts as a starting material for biosynthesis of NAG. The potential of D-GLU and its combination with mesalamine (5-ASA) was investigated in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-instigated IBD in Wistar rats. Standard and test drugs were given orally for five days to separate groups of rats. Colonic inflammation was evaluated by disease activity score rate (DASR), colon/body weight ratio, colon length, diameter, colon pH, histological injury and score. Inflammatory biomarkers IL-1β, TNF-α, along with reduced glutathione (GSH), and malondialdehyde (MDA) were assessed. Combination of D-GLU +5-ASA significantly ameliorated severity of colonic inflammation by lowering DASR (P < 0.001) and colon/body weight ratio (P < 0.001), restored the colonic architecture and suppressed the histopathological score (P < 0.001), along with the absence of major adverse reactions. The combination suppressed the levels of inflammatory markers (P < 0.001) and MDA (P < 0.001) while enhancing GSH level (P < 0.001). In comparison to individual 5-ASA and D-GLU, combination of drugs significantly diminished colitis severity through their combined anti-inflammatory and antioxidant effects by acting on multiple targets simultaneously. The combination holds remarkable potential in the management of IBD.

PMID:36154797 | DOI:10.1080/08923973.2022.2128370

Curr Neuropharmacol. 2022 Sep 22. doi: 10.2174/1570159X20666220922150456. Online ahead of print.

ABSTRACT

Pediatric malignant brain tumors represent the most frequent cause of cancer-related deaths in childhood. The triad of the therapeutic scheme of surgery, radiotherapy and chemotherapy has improved patient management, but with minimal improvement in patients' prognosis. Emerging molecular targets and mechanisms have pointed out novel approaches and schemes for pediatric brain tumor therapy, enabling personalized medical treatment. Advances in the field of epigenetics and their interplay with genetic changes have enriched our knowledge of the molecular heterogeneity of these neoplasms and have revealed important genes that affect crucial signaling pathways involved in tumor progression. The great potential of epigenetic therapy lies mainly in the widespread location and the reversibility of epigenetic alterations, proposing a wide range of targeting options, including the possible combination with chemo- and immunotherapy, significantly increasing their efficacy. Epigenetic drugs, including inhibitors of DNA methyltransferases, histone deacetylases and demethylases, are currently being tested in clinical trials on pediatric brain tumors. Additional novel epigenetic drugs include protein and enzyme inhibitors that modulate epigenetic modification pathways, such as Bromodomain and Extraterminal (BET) proteins, Cyclin-Dependent Kinase 9 (CDK9), AXL, Facilitates Chromatin Transcription (FACT), BMI1, and CREB Binding Protein (CBP) inhibitors, which can be used either as standalone or in combination with current treatment approaches. In this review, we discuss recent progress on epigenetic drugs that could be possibly used against the most common malignant tumors of childhood, such as medulloblastomas, high- grade gliomas and ependymomas.

PMID:36154607 | DOI:10.2174/1570159X20666220922150456

Expert Opin Drug Discov. 2022 Sep 26. doi: 10.1080/17460441.2022.2128333. Online ahead of print.

NO ABSTRACT

PMID:36154343 | DOI:10.1080/17460441.2022.2128333

Hum Mutat. 2022 Sep 24. doi: 10.1002/humu.24479. Online ahead of print.

ABSTRACT

A rare and fatal disease resembling mucopolysaccharidosis in infants, is caused by impaired intracellular endocytic trafficking due to deficiency of core components of the intracellular membrane-tethering protein complexes, HOPS and CORVET. Whole Exome Sequencing identified a novel VPS33A mutation in a patient suffering from a variant form of mucopolysaccharidosis. Electron and confocal microscopy, immunoblotting, and glycosphingolipid trafficking experiments were undertaken to investigate the effects of the mutant VPS33A in patient-derived skin fibroblasts. We describe an attenuated juvenile form of VPS33A-related syndrome - mucopolysaccharidosis plus in a man who is homozygous for a hitherto unknown missense mutation (NM_022916.4: c.599 G>C; NP_075067.2:p. Arg200Pro) in a conserved region of the VPS33A gene. Urinary glycosaminoglycan (GAG) analysis revealed increased heparan, dermatan sulphates and hyaluronic acid. We showed decreased abundance of VPS33A in patient derived fibroblasts and provided evidence that the p.Arg200Pro mutation leads to destabilisation of the protein and proteasomal degradation. As in the infantile form of mucopolysaccharidosis plus, the endocytic compartment in the fibroblasts also expanded - a phenomenon accompanied by increased endolysosomal acidification and impaired intracellular glycosphingolipid trafficking. Experimental treatment of the patient's cultured fibroblasts with the proteasome inhibitor, bortezomib, or exposure to an inhibitor of glucosylceramide synthesis, eliglustat, improved glycosphingolipid trafficking. To our knowledge this is the first report of an attenuated juvenile form of VPS33A insufficiency characterised by appreciable residual endosomal-lysosomal trafficking and a milder mucopolysaccharidosis plus than the disease in infants. Our findings expand the proof of concept of redeploying clinically approved drugs for therapeutic exploitation in patients with juvenile as well as infantile forms of mucopolysaccharidosis plus disease. This article is protected by copyright. All rights reserved.

PMID:36153662 | DOI:10.1002/humu.24479

Pathog Dis. 2022 Sep 24:ftac037. doi: 10.1093/femspd/ftac037. Online ahead of print.

ABSTRACT

Enterococci are important pathogens of nosocomial infections and are increasingly difficult to treat due to their intrinsic and acquired resistance to a range of antibiotics. Therefore, there is an urgent need to develop novel antibacterial agents, while drug repurposing is a promising approach to address this issue. Our study aimed to determine the antimicrobial efficacy of halicin against enterococci, and it has been found that the minimum inhibitory concentrations (MIC) of halicin against different strains of E. faecalis and E. faecium ranged from 4-8 μg/mL. In addition, the synergistic antibacterial effect between halicin and doxycycline (DOX) against enterococcus was observed through the checkerboard method, and it was found that halicin and DOX could significantly synergistically inhibit biofilm formation and eradicate preformed biofilms at sub-MICs. Moreover, the electron microscope results revealed that halicin could also disrupt the bacterial cell membrane at high concentrations. Furthermore, the cytotoxicity study confirmed that the combination of halicin and DOX has no significant cytotoxic effect on erythrocytes and other human-derived cells. Moreover, the mouse subcutaneous model and H&E staining showed that the combination of halicin and DOX could effectively reduce the bacterial load and inflammatory infiltration without obvious side effects. In nutshell, these results demonstrate the potential of halicin in combination with DOX as a novel therapy against infections by enterococcus.

PMID:36152595 | DOI:10.1093/femspd/ftac037

Methods Mol Biol. 2023;2576:495-504. doi: 10.1007/978-1-0716-2728-0_40.

ABSTRACT

A screening pool consisting of 617710 drug-like query molecules properly filtered from the ChEMBL database was employed for a ligand-based reverse screening toward the type 2 cannabinoid receptor (CB2) target. By using our recently developed PLATO polypharmacological web platform, 233 out of 617710 drug-like molecules were prioritized on the basis of the predicted bioactivity values, better than 0.2 μM with a probability of about 98%, toward the CB2 target. Building on these results, the occurrence of putative CB2-related targets was also investigated for prospective repurposing studies.

PMID:36152212 | DOI:10.1007/978-1-0716-2728-0_40

Environ Sci Pollut Res Int. 2022 Sep 24. doi: 10.1007/s11356-022-23142-1. Online ahead of print.

ABSTRACT

Fluvoxamine, a selective serotonin re uptake inhibitor, is used to treat depression. The aim of present study was to evaluate fluvoxamine in acute (egg albumin-induced inflammation) and chronic inflammatory rat models (formaldehyde and complete Freund's adjuvant (CFA)-induced arthritis). Fluvoxamine showed highly significant (p<0.001) protective effect at dose of 50 mg/kg orally with percentage suppression 21.3% as compared to disease control group in acute model. Likewise, formaldehyde-induced arthritic experiment confirmed the significant (p<0.001) anti-arthritic behavior, showed by fluvoxamine (50 mg/kg orally) throughout the study. Moreover, In CFA-induced model, the higher dose (fluvoxamine 50 mg/kg) exhibited highly significant (p<0.001) decrease in paw thickness and arthritic score with significant increase in weight of animals from 123.8± 1.934 g to 130.2± 1.655 g, significantly decreased the level of RF and CRP to level of 12.0±0.707 and 11.40±0.50 respectively and restoration of SOD, CAT (69.8±1.5, 72.0±1.4 respectively). Furthermore, the level of TNF-α, PGE2, and IL-1β (147.0±2.0, 406.8±2.5, and 93.8±1.3 respectively) in arthritic animals was reduced to significant (p<0.001) level (53.8±1.3, 205±3.6, and 42.0±1.4 respectively) after treatment with fluvoxamine. Furthermore, molecular docking of fluvoxamine against TNF-α, PGE2, and IL-1β protein targets showed good binding energies which hereby from computational studies proves our compound anti-inflammatory potential. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies reveled that fluvoxamine has very good pharmacokinetic profile with no specific hepatic toxicity and good absorption level. In addition, the skin sensitization test in vitro human cell line activation test (h-CLAT) and KeratinoSens have revealed that isolated flavone is not skin sensitive with confidence score of 59.6% and 91.6%. The current findings validated the anti-arthritic potential of fluvoxamine but it should be recommended for clinical investigation in future research.

PMID:36152089 | DOI:10.1007/s11356-022-23142-1

Brief Bioinform. 2022 Sep 23:bbac404. doi: 10.1093/bib/bbac404. Online ahead of print.

ABSTRACT

Drug discovery and development is a complex and costly process. Machine learning approaches are being investigated to help improve the effectiveness and speed of multiple stages of the drug discovery pipeline. Of these, those that use Knowledge Graphs (KG) have promise in many tasks, including drug repurposing, drug toxicity prediction and target gene-disease prioritization. In a drug discovery KG, crucial elements including genes, diseases and drugs are represented as entities, while relationships between them indicate an interaction. However, to construct high-quality KGs, suitable data are required. In this review, we detail publicly available sources suitable for use in constructing drug discovery focused KGs. We aim to help guide machine learning and KG practitioners who are interested in applying new techniques to the drug discovery field, but who may be unfamiliar with the relevant data sources. The datasets are selected via strict criteria, categorized according to the primary type of information contained within and are considered based upon what information could be extracted to build a KG. We then present a comparative analysis of existing public drug discovery KGs and an evaluation of selected motivating case studies from the literature. Additionally, we raise numerous and unique challenges and issues associated with the domain and its datasets, while also highlighting key future research directions. We hope this review will motivate KGs use in solving key and emerging questions in the drug discovery domain.

PMID:36151740 | DOI:10.1093/bib/bbac404

J Agric Food Chem. 2022 Sep 23. doi: 10.1021/acs.jafc.2c03441. Online ahead of print.

ABSTRACT

The inhibitory effect of tavaborole on the invasion of Botrytis cinerea in grapes and tomatoes, as well as the potential mechanism involved, was discovered in this study. Our findings showed that tavaborole inhibited Botrytis cinerea spore germination and mycelial expansion in vitro and that the control efficiency in vivo on fruit decay was dose-dependent, which was effective in reducing disease severity and maintaining the organoleptic quality of the fruit, such as reducing weight loss and retaining fruit hardness and titratable acid contents during storage. Furthermore, the precise mechanism of action was investigated further. Propidium iodide staining revealed that Botrytis cinerea treated with tavaborole lost membrane integrity. For further validation, cytoplasmic malondialdehyde accumulation and leakage of cytoplasmic constituents were determined. Notably, the inhibitory effect was also dependent on inhibiting the activities of aminoacyl-tRNA synthetases involved in the aminoacyl-tRNA biosynthesis pathway in Botrytis cinerea. The above findings concluded that tavaborole was effective against Botrytis cinerea infection in postharvest fruit, and a related mechanism was also discussed, which may provide references for the drug repurposing of tavaborole as a postharvest fungicide.

PMID:36149871 | DOI:10.1021/acs.jafc.2c03441

OMICS. 2022 Sep 23. doi: 10.1089/omi.2022.0097. Online ahead of print.

ABSTRACT

Metabolome is the end point of the genome-environment interplay, and enables an important holistic overview of individual adaptability and host responses to environmental, ecological, as well as endogenous changes such as disease. Pharmacometabolomics is the application of metabolome knowledge to decipher the mechanisms of interindividual and intraindividual variations in drug efficacy and safety. Pharmacometabolomics also contributes to prediction of drug treatment outcomes on the basis of baseline (predose) and postdose metabotypes through mathematical modeling. Thus, pharmacometabolomics is a strong asset for a diverse community of stakeholders interested in theory and practice of evidence-based and precision/personalized medicine: academic researchers, public health scholars, health professionals, pharmaceutical, diagnostics, and biotechnology industries, among others. In this expert review, we discuss pharmacometabolomics in four contexts: (1) an interdisciplinary omics tool and field to map the mechanisms and scale of interindividual variability in drug effects, (2) discovery and development of translational biomarkers, (3) advance digital biomarkers, and (4) empower drug repurposing, a field that is increasingly proving useful in the current era of Covid-19. As the applications of pharmacometabolomics are growing rapidly in the current postgenome era, next-generation proteomics and metabolomics follow the example of next-generation sequencing analyses. Pharmacometabolomics can also empower data reliability and reproducibility through multiomics integration strategies, which use each data layer to correct, connect with, and inform each other. Finally, we underscore here that contextual data remain crucial for precision medicine and drug development that stand the test of time and clinical relevance.

PMID:36149303 | DOI:10.1089/omi.2022.0097

Pharmaceutics. 2022 Aug 30;14(9):1828. doi: 10.3390/pharmaceutics14091828.

ABSTRACT

Drug interactions with other drugs are a well-known phenomenon. Similarly, however, pre-existing drug therapy can alter the course of diseases for which it has not been prescribed. We performed network analysis on drugs and their respective targets to investigate whether there are drugs or targets with protective effects in COVID-19, making them candidates for repurposing. These networks of drug-disease interactions (DDSIs) and target-disease interactions (TDSIs) revealed a greater share of patients with diabetes and cardiac co-morbidities in the non-severe cohort treated with dipeptidyl peptidase-4 (DPP4) inhibitors. A possible protective effect of DPP4 inhibitors is also plausible on pathophysiological grounds, and our results support repositioning efforts of DPP4 inhibitors against SARS-CoV-2. At target level, we observed that the target location might have an influence on disease progression. This could potentially be attributed to disruption of functional membrane micro-domains (lipid rafts), which in turn could decrease viral entry and thus disease severity.

PMID:36145576 | DOI:10.3390/pharmaceutics14091828

Pharmaceutics. 2022 Aug 24;14(9):1768. doi: 10.3390/pharmaceutics14091768.

ABSTRACT

The fast evolution of anti-tumor agents embodies a deeper understanding of cancer pathogenesis. To date, chemotherapy, targeted therapy, and immunotherapy are three pillars of the paradigm for cancer treatment. The success of immune checkpoint inhibitors (ICIs) implies that reinstatement of immunity can efficiently control tumor growth, invasion, and metastasis. However, only a fraction of patients benefit from ICI therapy, which turns the spotlight on developing safe therapeutic strategies to overcome the problem of an unsatisfactory response. Molecular-targeted agents were designed to eliminate cancer cells with oncogenic mutations or transcriptional targets. Intriguingly, accumulating shreds of evidence demonstrate the immunostimulatory or immunosuppressive capacity of targeted agents. By virtue of the high attrition rate and cost of new immunotherapy exploration, drug repurposing may be a promising approach to discovering combination strategies to improve response to immunotherapy. Indeed, many clinical trials investigating the safety and efficacy of the combination of targeted agents and immunotherapy have been completed. Here, we review and discuss the effects of targeted anticancer agents on the tumor immune microenvironment and explore their potential repurposed usage in cancer immunotherapy.

PMID:36145516 | DOI:10.3390/pharmaceutics14091768

Pharmaceuticals (Basel). 2022 Aug 27;15(9):1068. doi: 10.3390/ph15091068.

ABSTRACT

Due to the rapid, vast, and emerging global spread of the Coronavirus Disease 2019 (COVID-19) pandemic, many drugs were quickly repurposed in a desperate attempt to unveil a miracle drug. Ivermectin (IVM), an antiparasitic macrocyclic lactone, was tested and confirmed for its in vitro antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in early 2020. Along with its potential antiviral activity, the affordability and availability of IVM resulted in a wide public interest. Across the world, trials have put IVM to test for both the treatment and prophylaxis of COVID-19, as well as its potential role in combination therapy. Additionally, the targeted delivery of IVM was studied in animals and COVID-19 patients. Through this conducted literature review, the potential value and effectiveness of the repurposed antiparasitic agent in the ongoing global emergency were summarized. The reviewed trials suggested a value of IVM as a treatment in mild COVID-19 cases, though the benefit was not extensive. On the other hand, IVM efficacy as a prophylactic agent was more evident and widely reported. In the most recent trials, novel nasal formulations of IVM were explored with the hope of an improved optimized effect.

PMID:36145289 | DOI:10.3390/ph15091068

Molecules. 2022 Sep 14;27(18):5988. doi: 10.3390/molecules27185988.

ABSTRACT

The SARS-CoV-2 targets were evaluated for a set of FDA-approved drugs using a combination of drug repositioning and rigorous computational modeling methodologies such as molecular docking and molecular dynamics (MD) simulations followed by binding free energy calculations. Six FDA-approved drugs including, Ouabain, Digitoxin, Digoxin, Proscillaridin, Salinomycin and Niclosamide with promising anti-SARS-CoV-2 activity were screened in silico against four SARS-CoV-2 proteins-papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), SARS-CoV-2 main protease (Mpro), and adaptor-associated kinase 1 (AAK1)-in an attempt to define their promising targets. The applied computational techniques suggest that all the tested drugs exhibited excellent binding patterns with higher scores and stable complexes compared to the native protein cocrystallized inhibitors. Ouabain was suggested to act as a dual inhibitor for both PLpro and Mpro enzymes, while Digitoxin bonded perfectly to RdRp. In addition, Salinomycin targeted PLpro. Particularly, Niclosamide was found to target AAK1 with greater affinity compared to the reference drug. Our study provides comprehensive molecular-level insights for identifying or designing novel anti-COVID-19 drugs.

PMID:36144718 | DOI:10.3390/molecules27185988

Medicina (Kaunas). 2022 Sep 7;58(9):1239. doi: 10.3390/medicina58091239.

ABSTRACT

Over the last years, repurposed agents have provided growing evidence of fast implementation in oncology treatment such as certain antimalarial, anthelmintic, antibiotics, anti-inflammatory, antihypertensive, antihyperlipidemic, antidiabetic agents. In this study, the four agents of choice were present in our patients' daily treatment for nonmalignant-associated pathology and have known, light toxicity profiles. It is quite common for a given patient's daily administration schedule to include two or three of these drugs for the duration of their treatment. We chose to review the latest literature concerning metformin, employed as a first-line treatment for type 2 diabetes; mebendazole, as an anthelmintic; atorvastatin, as a cholesterol-lowering drug; propranolol, used in cardiovascular diseases as a nonspecific inhibitor of beta-1 and beta-2 adrenergic receptors. At the same time, certain key action mechanisms make them feasible antitumor agents such as for mitochondrial ETC inhibition, activation of the enzyme adenosine monophosphate-activated protein kinase, amelioration of endogenous hyperinsulinemia, inhibition of selective tyrosine kinases (i.e., VEGFR2, TNIK, and BRAF), and mevalonate pathway inhibition. Despite the abundance of results from in vitro and in vivo studies, the only solid data from randomized clinical trials confirm metformin-related oncological benefits for only a small subset of nondiabetic patients with HER2-positive breast cancer and early-stage colorectal cancer. At the same time, clinical studies confirm metformin-related detrimental/lack of an effect for lung, breast, prostate cancer, and glioblastoma. For atorvastatin we see a clinical oncological benefit in patients and head and neck cancer, with a trend towards radioprotection of critical structures, thus supporting the role of atorvastatin as a promising agent for concomitant association with radiotherapy. Propranolol-related increased outcomes were seen in clinical studies in patients with melanoma, breast cancer, and sarcoma.

PMID:36143915 | DOI:10.3390/medicina58091239

Int J Mol Sci. 2022 Sep 18;23(18):10933. doi: 10.3390/ijms231810933.

ABSTRACT

Despite the significant progress made towards comprehending the deregulated signatures in lung cancer, these vary from study to study. We reanalyzed 25 studies from the Gene Expression Omnibus (GEO) to detect and annotate co-deregulated signatures in lung cancer and in single-gene or single-drug perturbation experiments. We aimed to decipher the networks that these co-deregulated genes (co-DEGs) form along with their upstream regulators. Differential expression and upstream regulators were computed using Characteristic Direction and Systems Biology tools, including GEO2Enrichr and X2K. Co-deregulated gene expression profiles were further validated across different molecular and immune subtypes in lung adenocarcinoma (TCGA-LUAD) and lung adenocarcinoma (TCGA-LUSC) datasets, as well as using immunohistochemistry data from the Human Protein Atlas, before being subjected to subsequent GO and KEGG enrichment analysis. The functional alterations of the co-upregulated genes in lung cancer were mostly related to immune response regulating the cell surface signaling pathway, in contrast to the co-downregulated genes, which were related to S-nitrosylation. Networks of hub proteins across the co-DEGs consisted of overlapping TFs (SOX2, MYC, KAT2A) and kinases (MAPK14, CSNK2A1 and CDKs). Furthermore, using Connectivity Map we highlighted putative repurposing drugs, including valproic acid, betonicine and astemizole. Similarly, we analyzed the co-DEG signatures in single-gene and single-drug perturbation experiments in lung cancer cell lines. In summary, we identified critical co-DEGs in lung cancer providing an innovative framework for their potential use in developing personalized therapeutic strategies.

PMID:36142846 | DOI:10.3390/ijms231810933

Int J Mol Sci. 2022 Sep 13;23(18):10590. doi: 10.3390/ijms231810590.

ABSTRACT

Our structure-based virtual screening of the FDA-approved drug library has revealed that sonidegib, a smoothened antagonist clinically used to treat basal cell carcinoma, is a potential c-Jun N-terminal kinase 3 (JNK3) inhibitor. This study investigated the binding of sonidegib to JNK3 via 19F NMR and its inhibitory effect on JNK phosphorylation in BV2 cells. Pharmacological properties of sonidegib to exert anti-inflammatory and anti-migratory effects were also characterized. We found that sonidegib bound to the ATP binding site of JNK3 and inhibited JNK phosphorylation in BV2 cells, confirming our virtual screening results. Sonidegib also inhibited the phosphorylation of MKK4 and c-Jun, the upstream and downstream signals of JNK, respectively. It reduced the lipopolysaccharide (LPS)-induced production of pro-inflammatory factors, including interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO), and the expression of inducible NO synthase and cyclooxygenase-2. The LPS-induced cell migration was suppressed by sonidegib. Sonidegib inhibited the LPS-induced IκBα phosphorylation, thereby blocking NF-κB nuclear translocation. Consistent with these findings, orally administered sonidegib attenuated IL-6 and TNF-α levels in the brains of LPS-treated mice. Collectively, our results indicate that sonidegib suppresses inflammation and cell migration in LPS-treated BV2 cells and mice by inhibiting JNK and NF-κB signaling. Therefore, sonidegib may be implicated for drug repurposing to alleviate neuroinflammation associated with microglial activation.

PMID:36142500 | DOI:10.3390/ijms231810590

Healthcare (Basel). 2022 Sep 16;10(9):1784. doi: 10.3390/healthcare10091784.

ABSTRACT

Rare diseases are a group of uncommon diseases in the world population. To date, about 7000 rare diseases have been documented. However, most of them do not have a known treatment. As a result of the relatively low demand for their treatments caused by their scarce prevalence, the pharmaceutical industry has not sufficiently encouraged the research to develop drugs to treat them. This work aims to analyse potential drug-repositioning strategies for this kind of disease. Drug repositioning seeks to find new uses for existing drugs. In this context, it seeks to discover if rare diseases could be treated with medicines previously indicated to heal other diseases. Our approaches tackle the problem by employing computational methods that calculate similarities between rare and non-rare diseases, considering biological features such as genes, proteins, and symptoms. Drug candidates for repositioning will be checked against clinical trials found in the scientific literature. In this study, 13 different rare diseases have been selected for which potential drugs could be repositioned. By verifying these drugs in the scientific literature, successful cases were found for 75% of the rare diseases studied. The genetic associations and phenotypical features of the rare diseases were examined. In addition, the verified drugs were classified according to the anatomical therapeutic chemical (ATC) code to highlight the types with a higher predisposition to be repositioned. These promising results open the door for further research in this field of study.

PMID:36141396 | DOI:10.3390/healthcare10091784

Biomedicines. 2022 Sep 19;10(9):2326. doi: 10.3390/biomedicines10092326.

ABSTRACT

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a "computer-aided drug repurposing" approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and in-house academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity. Our computational protocol showed to be a robust approach for the identification of hits with drug-like scaffolds as possible inhibitors of the TLR4 innate immune pathways. Our collaborative work broadens the chemical diversity for inspiration of new classes of TLR4 modulators.

PMID:36140427 | DOI:10.3390/biomedicines10092326

Cancers (Basel). 2022 Sep 10;14(18):4401. doi: 10.3390/cancers14184401.

ABSTRACT

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients' outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

PMID:36139561 | DOI:10.3390/cancers14184401