Cancers (Basel). 2023 Oct 25;15(21):5136. doi: 10.3390/cancers15215136.

ABSTRACT

High-grade serous ovarian cancer (HGSOC) accounts for 70% of ovarian cancer cases, and the survival rate remains remarkably low due to the lack of effective long-term consolidation therapies. Clinical remission can be temporarily induced by platinum-based chemotherapy, but death subsequently results from the extensive growth of a platinum-resistant component of the tumor. This work explores a novel treatment against HGSOC using the gold complex auranofin (AF). AF primarily functions as a pro-oxidant by inhibiting thioredoxin reductase (TrxR), an antioxidant enzyme overexpressed in ovarian cancer. We investigated the effect of AF on TrxR activity and the various mechanisms of cytotoxicity using HGSOC cells that are clinically sensitive or resistant to platinum. In addition, we studied the interaction between AF and another pro-oxidant, L-buthionine sulfoximine (L-BSO), an anti-glutathione (GSH) compound. We demonstrated that AF potently inhibited TrxR activity and reduced the vitality and viability of HGSOC cells regardless of their sensitivities to platinum. We showed that AF induces the accumulation of reactive oxygen species (ROS), triggers the depolarization of the mitochondrial membrane, and kills HGSOC cells by inducing apoptosis. Notably, AF-induced cell death was abrogated by the ROS-scavenger N-acetyl cysteine (NAC). In addition, the lethality of AF was associated with the activation of caspases-3/7 and the generation of DNA damage, effects that were also prevented by the presence of NAC. Finally, when AF and L-BSO were combined, we observed synergistic lethality against HGSOC cells, which was mediated by a further increase in ROS and a decrease in the levels of the antioxidant GSH. In summary, our results support the concept that AF can be used alone or in combination with L-BSO to kill HGSOC cells regardless of their sensitivity to platinum, suggesting that the depletion of antioxidants is an efficient strategy to mitigate the course of this disease.

PMID:37958311 | DOI:10.3390/cancers15215136

Mol Psychiatry. 2023 Nov 13. doi: 10.1038/s41380-023-02314-6. Online ahead of print.

ABSTRACT

The stimulant methylphenidate (MPH) and the non-stimulant atomoxetine (ATX) are frequently used for the treatment of attention-deficit/hyperactivity disorder (ADHD); however, the function of these drugs in different types of brain cells and their effects on related genes remain largely unknown. To address these questions, we built a pipeline for the simultaneous examination of the activity behavior and transcriptional responses of Drosophila melanogaster at single-cell resolution following drug treatment. We selected the Drosophila with significantly increased locomotor activities (hyperactivity-like behavior) following the administration of each drug in comparison with the control (same food as the drug-treated groups with 5% sucrose, yeast, and blue food dye solution) using EasyFlyTracker. Subsequently, single cell RNA sequencing (scRNASEQ) was used to capture the transcriptome of 82,917 cells, unsupervised clustering analysis of which yielded 28 primary cell clusters representing the major cell types in adult Drosophila brain. Indeed, both neuronal and glial cells responded to MPH and ATX. Further analysis of differentially expressed genes (DEGs) revealed distinct transcriptional changes associated with these two drugs, such as two well-studied dopamine receptor genes (Dop2R and DopEcR) were responsive to MPH but not to ATX at their optimal doses, in addition to genes involved in dopamine metabolism pathways such as Syt1, Sytalpha, Syt7, and Ih in different cell types. More importantly, MPH also suppressed the expression of genes encoding other neurotransmitter receptors and synaptic signaling molecules in many cell types, especially those for Glu and GABA, while the responsive effects of ATX were much weaker. In addition to monoaminergic neuronal transmitters, other neurotransmitters have also shown a similar pattern with respect to a stronger effect associated with MPH than with ATX. Moreover, we identified four distinct glial cell subtypes responsive to the two drugs and detected a greater number of differentially expressed genes associated with ensheathing and astrocyte-like glia. Furthermore, our study provides a rich resource of candidate target genes, supported by drug set enrichment analysis (P = 2.10E-4; hypergeometric test), for the further exploration of drug repurposing. The whole list of candidates can be found at ADHDrug ( http://adhdrug.cibr.ac.cn/ ). In conclusion, we propose a fast and cost-efficient pipeline to explore the underlying molecular mechanisms of ADHD drug treatment in Drosophila brain at single-cell resolution, which may further facilitate drug repurposing applications.

PMID:37957291 | DOI:10.1038/s41380-023-02314-6

Planta Med. 2023 Nov 13. doi: 10.1055/a-2209-6357. Online ahead of print.

ABSTRACT

In early 2020, a global pandemic was announced due to the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), known to cause COVID-19. Despite worldwide efforts, there are only limited options regarding antiviral drug treatments for COVID-19. Although the vaccines are now available, issues such as declining efficacy against different SARS-CoV-2 variants and aging of vaccine-induced immunity highlight the importance of finding more antiviral drugs as a second line of defense against the disease. Drug repurposing has been used to rapidly find COVID-19 therapeutic options. Due to the lack of clinical evidence for the therapeutic benefits and certain serious side effects of repurposed antivirals, the search for an antiviral drug against SARS-CoV-2 with fewer side effects continues. In recent years, numerous studies have included antiviral chemicals from a variety of plant species. A better knowledge of the possible antiviral natural products and their mechanism against SARS-CoV-2 will help to develop stronger and more targeted direct-acting antiviral agents. The aim of the present study was to compile the current data on potential plant metabolites that can be investigated in COVID-19 drug discovery and development. This review represents a collection of plant secondary metabolites and their mode of action against SARS-CoV and SARS-CoV-2.

PMID:37956978 | DOI:10.1055/a-2209-6357

Arch Biochem Biophys. 2023 Nov 11:109820. doi: 10.1016/j.abb.2023.109820. Online ahead of print.

ABSTRACT

The nucleocapsid (N) protein of SARS-CoV-2 plays a pivotal role in encapsulating the viral genome. Developing antiviral treatments for SARS-CoV-2 is imperative due to the diminishing immunity of the available vaccines. This study targets the RNA-binding site located in the N-terminal domain (NTD) of the N-protein to identify the potential antiviral molecules against SARS-CoV-2. A structure-based repurposing approach identified the twelve high-affinity molecules from FDA-approved drugs, natural products, and the LOPAC1280 compound libraries that precisely bind to the RNA binding site within the NTD. The interaction of these potential antiviral agents with the purified NTD protein was thermodynamically characterized using isothermal titration calorimetry (ITC). A fluorescence-based plate assay to assess the RNA binding inhibitory activity of small molecules against the NTD has been employed, and the selected compounds exhibited significant RNA binding inhibition with calculated IC50 values ranging from 8.8 μM to 15.7 μM. Furthermore, the antiviral efficacy of these compounds was evaluated using in vitro cell-based assays targeting the replication of SARS-CoV-2. Remarkably, two compounds, Telmisartan and BMS-189453, displayed potential antiviral activity against SARS-CoV-2, with EC50 values of approximately 1.02 μM and 0.98 μM, and a notable selective index of >98 and > 102, respectively. This study gives valuable insight into developing therapeutic interventions against SARS-CoV-2 by targeting the N-protein, a significant effort given the global public health concern posed due to the virus re-emergence and long COVID-19 disease.

PMID:37956938 | DOI:10.1016/j.abb.2023.109820

Cureus. 2023 Oct 11;15(10):e46860. doi: 10.7759/cureus.46860. eCollection 2023 Oct.

ABSTRACT

Rare genetic disorders (RDs), characterized by their low prevalence and diagnostic complexities, present significant challenges to healthcare systems. This article explores the transformative impact of artificial intelligence (AI) and machine learning (ML) in addressing these challenges. It emphasizes the need for accurate and early diagnosis of RDs, often hindered by genetic and clinical heterogeneity. This article discusses how AI and ML are reshaping healthcare, providing examples of their effectiveness in disease diagnosis, prognosis, image analysis, and drug repurposing. It highlights AI's ability to efficiently analyze extensive datasets and expedite diagnosis, showcasing case studies like Face2Gene. Furthermore, the article explores how AI tailors treatment plans for RDs, leveraging ML and deep learning (DL) to create personalized therapeutic regimens. It emphasizes AI's role in drug discovery, including the identification of potential candidates for rare disease treatments. Challenges and limitations related to AI in healthcare, including ethical, legal, technical, and human aspects, are addressed. This article underscores the importance of data ethics, privacy, and algorithmic fairness, as well as the need for standardized evaluation techniques and transparency in AI research. It highlights second-generation AI systems that prioritize patient-centric care, efficient patient recruitment for clinical trials, and the significance of high-quality data. The integration of AI with telemedicine, the growth of health databases, and the potential for personalized therapeutic recommendations are identified as promising directions for the field. In summary, this article provides a comprehensive exploration of how AI and ML are revolutionizing the diagnosis and treatment of RDs, addressing challenges while considering ethical implications in this rapidly evolving healthcare landscape.

PMID:37954711 | PMC:PMC10636514 | DOI:10.7759/cureus.46860

J Neurochem. 2023 Nov 12. doi: 10.1111/jnc.16005. Online ahead of print.

ABSTRACT

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs-based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs-based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS-specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double-blind, randomized, placebo-controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient-derived iPSCs-motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA-seq data showed that ROPI treatment suppressed the sterol regulatory element-binding protein 2-dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

PMID:37952981 | DOI:10.1111/jnc.16005

J Autoimmun. 2023 Nov 10;142:103124. doi: 10.1016/j.jaut.2023.103124. Online ahead of print.

ABSTRACT

Giant cell arteritis (GCA) is a systemic vasculitis mediated by an aberrant immunological response against the blood vessel wall. Although the pathogenic mechanisms that drive GCA have not yet been elucidated, there is strong evidence that CD4+ T cells are key drivers of the inflammatory process occurring in this vasculitis. The aim of this study was to further delineate the role of CD4+ T cells in GCA by applying single-cell RNA sequencing and T cell receptor (TCR) repertoire profiling to 114.799 circulating CD4+ T cells from eight GCA patients in two different clinical states, active and in remission, and eight healthy controls. Our results revealed an expansion of cytotoxic CD4+ T lymphocytes (CTLs) in active GCA patients, which expressed higher levels of cytotoxic and chemotactic genes when compared to patients in remission and controls. Accordingly, differentially expressed genes in CTLs of active patients were enriched in pathways related to granzyme-mediated apoptosis, inflammation, and the recruitment of different immune cells, suggesting a role of this cell type in the inflammatory and vascular remodelling processes occurring in GCA. CTLs also exhibited a higher clonal expansion in active patients with respect to those in remission. Drug repurposing analysis prioritized maraviroc, which targeted CTLs, as potentially repositionable for this vasculitis. In addition, effector regulatory T cells (Tregs) were decreased in GCA and showed lower expression of genes involved in their suppressive activity. These findings provide further insights into the pathogenic role of CD4+ T cells in GCA and suggest targeting CTLs as a potential therapeutic option.

PMID:37952293 | DOI:10.1016/j.jaut.2023.103124

Folia Microbiol (Praha). 2023 Nov 11. doi: 10.1007/s12223-023-01104-5. Online ahead of print.

ABSTRACT

Cryptococcus neoformans is an encapsulated yeast that can cause cryptococcosis and cryptococcal meningitis, which conventional treatment involves antifungal drugs such as polyenes, flucytosine, azoles, and their combinations. However, the high cost, toxicity, and increase in fungi resistance to antifungal agents stimulate the search for therapeutic strategies such as drug repurposing and combination therapy. This study evaluated the activity of the antihypertensive verapamil (VEH) alone and combined with amphotericin B (AmB) against C. neoformans. VEH exhibited antifungal activity against C. neoformans with minimum inhibitory concentration and minimum fungicidal concentration of 118 µg per mL. The combination of VEH and AmB exhibited synergism, reducing at least eightfold both drugs' concentrations. Moreover, the combination decreased the size and glucuronoxylomannnan content of C. neoformans capsule. However, no difference was observed in ergosterol levels of C. neoformans after treatment with VEH and AmB in combination. Altogether, VEH in combination with AmB exhibits potential as a candidate as for the development of anti-cryptococcal drug.

PMID:37950840 | DOI:10.1007/s12223-023-01104-5

Exp Parasitol. 2023 Nov 8:108641. doi: 10.1016/j.exppara.2023.108641. Online ahead of print.

ABSTRACT

Visceral cestodiases, like echinococcoses and cysticercoses, are zoonoses of worldwide distribution and are responsible for public health problems in many countries, especially in underdeveloped regions. Current treatments have low efficiency and there are few drugs currently in use for chemotherapy, making the development of new anthelmintics an urgent matter. The nucleotide salvage pathways are the only ones available for nucleotide synthesis in cestodes and other parasitic helminths, and, here, we used in silico approaches to assess the potential of the enzymes in these pathways as targets for drug repurposing as anthelminthics. First, a genomic survey allowed to identify a repertoire of 28 enzymes of the purine and pyrimidine salvage pathways from the cestode Echinococcus granulosus sensu stricto. Regarding purines, the parasite relies on salvaging free bases rather than salvaging nucleosides. Pyrimidines, on the other hand, can be salvaged from both bases and nucleosides. Druggability of the parasite enzymes was assessed, as well as the availability of commercial inhibitors for them. Druggable enzymes were then ranked according to their potential for drug repurposing and the 17 most promising enzymes were selected for evolutionary analyses. The constructed phylogenetic trees allowed to assess the degree of conservation among ortholog enzymes from parasitic helminths and their mammalian hosts. Positive selection is absent in all assessed flatworm enzymes. A potential target enzyme for drug repurposing, ribonucleotide reductase (RNR), was selected for further assessment. RNR 3D-modelling showed structural similarities between the E. granulosus and the human orthologs suggesting that inhibitors of the human RNR should be effective against the E. granulosus enzyme. In line with that, E. granulosus protoscolices treated in vitro with the inhibitor hydroxyurea had their viability and DNA synthesis reduced. These results are consistent with nucleotide synthesis inhibition and confirm the potential of a nucleotide salvage inhibitors for repurposing as an anthelmintic.

PMID:37949425 | DOI:10.1016/j.exppara.2023.108641

Assay Drug Dev Technol. 2023 Nov 10. doi: 10.1089/adt.2023.125. Online ahead of print.

NO ABSTRACT

PMID:37948550 | DOI:10.1089/adt.2023.125

J Biomol Struct Dyn. 2023 Nov 10:1-17. doi: 10.1080/07391102.2023.2280677. Online ahead of print.

ABSTRACT

Increased concentrations of the fibronectin glycoprotein can cause ectopic tissue growth patients with endometriosis and the formation of various cancerous tumors. Furthermore, fibronectin binding to its receptors from the EDA (Extra Domain A) region contributes to promote tumorigenesis, metastasis and vasculogenesis. Thus, the EDA region can be considered a unique target for therapeutic intervention. Therefore, the present study used computational methods to identify the best fibronectin inhibitor(s) among FDA-approved drugs. First, docking-based virtual screening was performed using PyRx 0.8. Next, FDA-approved drugs that obtained favorable results in the docking phase were selected for further studies and analysis using molecular dynamics (MD) simulation. The preliminary findings of the virtual screening showed that 17 FDA-approved drugs (from 2471) had more favorable energy with their binding energy less than -9 kcal/mol. The MD simulation results of these 17 drugs showed that Avapritinib had a lower RMSD value and higher binding energy and hydrogen bonding than the other complexes in the EDA domain. Also, analyses related to the second structure changes displayed that Avapritinib in the EDA domain led to more changes in the second structure. According to the results, the anticancer drug Avapritinib forms a more stable complex with fibronectin than other FDA-approved drugs. Furthermore, this drug leads to more changes in the second EDA structure, which may have more serious potential for inhibiting EDA fibronectin.Communicated by Ramaswamy H. Sarma.

PMID:37948310 | DOI:10.1080/07391102.2023.2280677

J Biomol Struct Dyn. 2023 Nov 10:1-19. doi: 10.1080/07391102.2023.2279699. Online ahead of print.

ABSTRACT

The spread of drug-resistant strains of tuberculosis has hampered efforts to control the disease worldwide. The Mycobacterium tuberculosis cell wall envelope is dynamic, with complex features that protect it from the host immunological response. As a result, the bacterial cell wall components represent a potential target for drug discovery. Protein-protein interaction networks (PPIN) are critical for understanding disease conditions and identifying precise therapeutic targets. We used a rational theoretical approach by constructing a PPIN with the proteins involved in cell wall biosynthesis. The PPIN was constructed through the STRING database and embB was identified as a key protein by using four topological measures, betweenness, closeness, degree, and eigenvector, in the CytoNCA tool in Cytoscape. The 'Drug repurposing' approach was employed to find suitable inhibitors against embB. We used the Schrödinger suites for molecular docking, molecular dynamics simulation, and binding free energy calculations to validate the binding of protein with the ligand. FDA-approved drugs from the ZINC database and DrugBank were screened against embB (PDB ID: 7BVF) using high-throughput virtual screening, standard precision, and extra precision docking. The drugs were screened based on the XP docking score of the standard drug ethambutol. Accordingly, from the top five hits, azilsartan and dihydroergotamine were selected based on the binding free energy values and were further subjected to Molecular Dynamics Simulation studies for 100 ns. Our study confirms that Azilsartan and Dihydroergotamine form stable complexes with embB and can be used as potential lead molecules based on further in vitro and in vivo experimental validation.Communicated by Ramaswamy H. Sarma.

PMID:37948198 | DOI:10.1080/07391102.2023.2279699

Hum Mol Genet. 2023 Nov 8:ddad192. doi: 10.1093/hmg/ddad192. Online ahead of print.

ABSTRACT

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder caused by the reduction of survival of motor neuron (SMN) protein levels. Although three SMN-augmentation therapies are clinically approved that significantly slow down disease progression, they are unfortunately not cures. Thus, complementary SMN-independent therapies that can target key SMA pathologies and that can support the clinically approved SMN-dependent drugs are the forefront of therapeutic development. We have previously demonstrated that prednisolone, a synthetic glucocorticoid (GC) improved muscle health and survival in severe Smn-/-;SMN2 and intermediate Smn2B/- SMA mice. However, long-term administration of prednisolone can promote myopathy. We thus wanted to identify genes and pathways targeted by prednisolone in skeletal muscle to discover clinically approved drugs that are predicted to emulate prednisolone's activities. Using an RNA-sequencing, bioinformatics, and drug repositioning pipeline on skeletal muscle from symptomatic prednisolone-treated and untreated Smn-/-; SMN2 SMA and Smn+/-; SMN2 healthy mice, we identified molecular targets linked to prednisolone's ameliorative effects and a list of 580 drug candidates with similar predicted activities. Two of these candidates, metformin and oxandrolone, were further investigated in SMA cellular and animal models, which highlighted that these compounds do not have the same ameliorative effects on SMA phenotypes as prednisolone; however, a number of other important drug targets remain. Overall, our work further supports the usefulness of prednisolone's potential as a second-generation therapy for SMA, identifies a list of potential SMA drug treatments and highlights improvements for future transcriptomic-based drug repositioning studies in SMA.

PMID:37947217 | DOI:10.1093/hmg/ddad192

Curr Med Chem. 2023 Nov 8. doi: 10.2174/0109298673266470231023110841. Online ahead of print.

ABSTRACT

Drug development is a complex and expensive process that involves extensive research and testing before a new drug can be approved for use. This has led to a limited availability of potential therapeutics for many diseases. Despite significant advances in biomedical science, the process of drug development remains a bottleneck, as all hypotheses must be tested through experiments and observations, which can be time-- consuming and costly. To address this challenge, drug repurposing has emerged as an innovative strategy for finding new uses for existing medications that go beyond their original intended use. This approach has the potential to speed up the drug development process and reduce costs, making it an attractive option for pharmaceutical companies and researchers alike. It involves the identification of existing drugs or compounds that have the potential to be used for the treatment of a different disease or condition. This can be done through a variety of approaches, including screening existing drugs against new disease targets, investigating the biological mechanisms of existing drugs, and analyzing data from clinical trials and electronic health records. Additionally, repurposing drugs can lead to the identification of new therapeutic targets and mechanisms of action, which can enhance our understanding of disease biology and lead to the development of more effective treatments. Overall, drug repurposing is an exciting and promising area of research that has the potential to revolutionize the drug development process and improve the lives of millions of people around the world. The present review provides insights on types of interaction, approaches, availability of databases, applications and limitations of drug repurposing.

PMID:37946344 | DOI:10.2174/0109298673266470231023110841

J Transl Med. 2023 Nov 8;21(1):796. doi: 10.1186/s12967-023-04695-2.

ABSTRACT

BACKGROUND: Epilepsy affects over 65 million people worldwide and significantly burdens patients, caregivers, and society. Drug-resistant epilepsy occurs in approximately 30% of patients and growing evidence indicates that oxidative stress contributes to the development of such epilepsies. Activation of the Nrf2 pathway, which is involved in cellular defense, offers a potential strategy for reducing oxidative stress and epilepsy treatment. Dimethyl fumarate (DMF), an Nrf2 activator, exhibits antioxidant and anti-inflammatory effects and is used to treat multiple sclerosis.

METHODS: The expression of Nrf2 and its related genes in vehicle or DMF treated rats were determined via RT-PCR and Western blot analysis. Neuronal cell death was evaluated by immunohistochemical staining. The effects of DMF in preventing the onset of epilepsy and modifying the disease were investigated in the kainic acid-induced status epilepticus model of temporal lobe epilepsy in rats. The open field, elevated plus maze and T-Maze spontaneous alteration tests were used for behavioral assessments.

RESULTS: We demonstrate that administration of DMF following status epilepticus increased Nrf2 activity, attenuated status epilepticus-induced neuronal cell death, and decreased seizure frequency and the total number of seizures compared to vehicle-treated animals. Moreover, DMF treatment reversed epilepsy-induced behavioral deficits in the treated rats. Moreover, DMF treatment even when initiated well after the diagnosis of epilepsy, reduced symptomatic seizures long after the drug was eliminated from the body.

CONCLUSIONS: Taken together, these findings suggest that DMF, through the activation of Nrf2, has the potential to serve as a therapeutic target for preventing epileptogenesis and modifying epilepsy.

PMID:37940957 | PMC:PMC10634153 | DOI:10.1186/s12967-023-04695-2

Protein J. 2023 Nov 8. doi: 10.1007/s10930-023-10163-z. Online ahead of print.

ABSTRACT

AKR1B1 and AKR1B10 are important members of aldo-keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of - 30.84 and - 29.36 kJ/mol respectively. To validate the stability of the protein-ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

PMID:37940790 | DOI:10.1007/s10930-023-10163-z

Trends Pharmacol Sci. 2023 Nov 6:S0165-6147(23)00210-9. doi: 10.1016/j.tips.2023.09.008. Online ahead of print.

ABSTRACT

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with uncertain origins. Understanding of the mechanisms underlying ASD remains limited, and treatments are lacking. Genetic diversity complicates drug development. Given the complexity and severity of ASD symptoms and the rising number of diagnoses, exploring novel therapeutic strategies is essential. Here, we focus on shared molecular pathways between ASD and cancer and highlight recent progress on the repurposing of cancer drugs for ASD treatment, such as mTOR inhibitors, histone deacetylase inhibitors, and anti-inflammatory agents. We discuss how to improve trial design considering drug dose and patient age. Lastly, the discussion explores the critical aspects of side effects, commercial factors, and the efficiency of drug-screening pipelines; all of which are essential considerations in the pursuit of repurposing cancer drugs for addressing core features of ASD.

PMID:37940430 | DOI:10.1016/j.tips.2023.09.008

Trends Cancer. 2023 Nov 6:S2405-8033(23)00215-7. doi: 10.1016/j.trecan.2023.10.004. Online ahead of print.

ABSTRACT

The prognosis of the patients with medulloblastoma who relapse after initial treatment including radiotherapy remains dismal. A recent study by Peyrl et al. in JAMA Oncology suggests that the metronomic multidrug combination used in the medulloblastoma European multitarget metronomic antiangiogenic trial (MEMMAT) given at relapse can improve long-term survival.

PMID:37940401 | DOI:10.1016/j.trecan.2023.10.004

Br J Clin Pharmacol. 2023 Nov 8. doi: 10.1111/bcp.15957. Online ahead of print.

ABSTRACT

Medications have been a part of space travel dating back to the Apollo missions. Currently, medical kits aboard the International Space Station (ISS) contain medications and supplies to treat a variety of possible medical events. As we prepare for more distant exploration missions to Mars and beyond, risk management planning for astronaut healthcare should include the assembly of a medication formulary that is comprehensive enough to prevent or treat anticipated medical events, remains safe and chemically stable, and retains sufficient potency to last for the duration of the mission. Emerging innovation and technologies in pharmaceutical development, delivery, quality maintenance, and validation offer promise for addressing these challenges. The present editorial will summarize the current state of knowledge regarding innovative formulary optimization strategies, pharmaceutical stability assessment techniques, and storage and packaging solutions that could enhance drug safety and efficacy for future exploration spaceflight missions.

PMID:37940128 | DOI:10.1111/bcp.15957

J Control Release. 2023 Nov 6:S0168-3659(23)00711-3. doi: 10.1016/j.jconrel.2023.10.050. Online ahead of print.

ABSTRACT

Despite tremendous global efforts since the beginning of the COVID-19 pandemic, still only a limited number of prophylactic and therapeutic options are available. Although vaccination is the most effective measure in preventing morbidity and mortality, there is a need for safe and effective post-infection treatment medication. In this study, we explored a pipeline of 21 potential candidates, examined in the Calu-3 cell line for their antiviral efficacy, for drug repurposing. Ralimetinib and nafamostat, clinically used drugs, have emerged as attractive candidates. Due to the inherent limitations of the selected drugs, we formulated targeted liposomes suitable for both systemic and intranasal administration. Non-targeted and targeted nafamostat liposomes (LipNaf) decorated with an Apolipoprotein B peptide (ApoB-P) as a specific lung-targeting ligand were successfully developed. The developed liposomal formulations of nafamostat were found to possess favorable physicochemical properties including nano size (119-147 nm), long-term stability of the normally rapidly degrading compound in aqueous solution, negligible leakage from the liposomes upon storage, and a neutral surface charge with low polydispersity index (PDI). Both nafamostat and ralimetinib liposomes showed good cellular uptake and lack of cytotoxicity, and non-targeted LipNaf demonstrated enhanced accumulation in the lungs following intranasal (IN) administration in non-infected mice. LipNaf retained its anti-SARS-CoV 2 activity in Calu 3 cells with only a modest decrease, exhibiting complete inhibition at concentrations >100 nM. IN, but not intraperitoneal (IP) treatment with targeted LipNaf resulted in trend to reduced viral load in the lungs of K18-hACE2 mice compared to targeted empty Lip. Nevertheless, upon removal of outlier data, a statistically significant 1.9-fold reduction in viral load was achieved. This observation further highlights the importance of a targeted delivery into the respiratory tract. In summary, we were able to demonstrate a proof-of-concept of drug repurposing by liposomal formulations with anti-SARS-CoV-2 activity. The biodistribution and bioactivity studies with LipNaf suggest an IN or inhalation route of administration for optimal therapeutic efficacy.

PMID:37939853 | DOI:10.1016/j.jconrel.2023.10.050