Curr Opin Crit Care. 2023 Jan 31. doi: 10.1097/MCC.0000000000001020. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Muscle wasting in critical illness has proven to be refractory to physical rehabilitation, and to conventional nutritional strategies. This presents one of the central challenges to critical care medicine in the 21st century. Novel strategies are needed, that facilitate nutritional interventions, identify patients that will benefit and have measurable, relevant benefits.

RECENT FINDINGS: Drug repurposing was demonstrated to be a powerful technique in the coronavirus disease 2019 pandemic, and may have similar applications to address the metabolic derangements of critical illness. Newer biological signatures may aid the application of these techniques and the association between changes in urea:creatinine ratio and the development of skeletal muscle wasting is increasing. A core outcome set for nutrition interventions in critical illness was published earlier this year supported by multiple international societies that should be adopted by future nutrition trials aiming to attenuate muscle wasting.

SUMMARY: The evidence base for the lack of efficacy for conventional nutritional strategies in preventing muscle wasting in critically ill patients continues to grow. Novel strategies such as metabolic modulators, patient level biological signatures of nutritional response and standardized outcome for measurements of efficacy will be central to future research and clinical care of the critically ill patient.

PMID:36762680 | DOI:10.1097/MCC.0000000000001020

J Med Microbiol. 2023 Feb;72(2). doi: 10.1099/jmm.0.001664.

ABSTRACT

Candida spp. infections are a serious health problem, especially in patients with risk factors. The acquisition of resistance, often associated with biofilm production, makes treatment more difficult due to the reduced effectiveness of available antifungals. Drug repurposing is a good alternative for the treatment of infections by Candida spp. biofilms. The present study evaluated the in vitro antibiofilm activity of sertraline in reducing the cell viability of forming and matured biofilms, in addition to elucidating whether effective concentrations are safe. Sertraline reduced biofilm cell viability by more than 80 % for all Candida species tested, acting at low and safe concentrations, both on mature biofilm and in preventing its formation, even the one with highest virulence. Its preventive mechanism seemed to be related to binding with ALS3. These data indicate that sertraline is a promising drug with anticandidal biofilm potential in safe doses. However, further studies are needed to elucidate the antibiofilm mechanism and possible application of pharmaceutical forms.

PMID:36762524 | DOI:10.1099/jmm.0.001664

Front Oncol. 2023 Jan 25;13:1096081. doi: 10.3389/fonc.2023.1096081. eCollection 2023.

ABSTRACT

INTRODUCTION: Integrating interaction data with biological knowledge can be a critical approach for drug development or drug repurposing. In this context, host-pathogen-protein-protein interaction (HP-PPI) networks are useful instrument to uncover the phenomena underlying therapeutic effects in infectious diseases, including cervical cancer, which is almost exclusively due to human papillomavirus (HPV) infections. Cervical cancer is one of the second leading causes of death, and HPV16 and HPV18 are the most common subtypes worldwide. Given the limitations of traditionally used virus-directed drug therapies for infectious diseases and, at the same time, recent cancer statistics for cervical cancer cases, the need for innovative treatments becomes clear.

METHODS: Accordingly, in this study, we emphasize the potential of host proteins as drug targets and identify promising host protein candidates for cervical cancer by considering potential differences between HPV subtypes (i.e., HPV16 and HPV18) within a novel bioinformatics framework that we have developed. Subsequently, subtype-specific HP-PPI networks were constructed to obtain host proteins. Using this framework, we next selected biologically significant host proteins. Using these prominent host proteins, we performed drug repurposing analysis. Finally, by following our framework we identify the most promising host-oriented drug candidates for cervical cancer.

RESULTS: As a result of this framework, we discovered both previously associated and novel drug candidates, including interferon alfacon-1, pimecrolimus, and hyaluronan specifically for HPV16 and HPV18 subtypes, respectively.

DISCUSSION: Consequently, with this study, we have provided valuable data for further experimental and clinical efforts and presented a novel bioinformatics framework that can be applied to any infectious disease.

PMID:36761959 | PMC:PMC9905826 | DOI:10.3389/fonc.2023.1096081

Nat Cancer. 2023 Feb 9. doi: 10.1038/s43018-022-00508-5. Online ahead of print.

ABSTRACT

BRAFV600E mutation confers a poor prognosis in metastatic colorectal cancer (CRC) despite combinatorial targeted therapies based on the latest understanding of signaling circuitry. To identify parallel resistance mechanisms induced by BRAF-MEK-EGFR co-targeting, we used a high-throughput kinase activity mapping platform. Here we show that SRC kinases are systematically activated in BRAFV600E CRC following targeted inhibition of BRAF ± EGFR and that coordinated targeting of SRC with BRAF ± EGFR increases treatment efficacy in vitro and in vivo. SRC drives resistance to BRAF ± EGFR targeted therapy independently of ERK signaling by inducing transcriptional reprogramming through β-catenin (CTNNB1). The EGFR-independent compensatory activation of SRC kinases is mediated by an autocrine prostaglandin E2 loop that can be blocked with cyclooxygenase-2 (COX2) inhibitors. Co-targeting of COX2 with BRAF + EGFR promotes durable suppression of tumor growth in patient-derived tumor xenograft models. COX2 inhibition represents a drug-repurposing strategy to overcome therapeutic resistance in BRAFV600E CRC.

PMID:36759733 | DOI:10.1038/s43018-022-00508-5

Int J Oral Sci. 2023 Feb 8;15(1):8. doi: 10.1038/s41368-022-00213-0.

ABSTRACT

Fusobacterium nucleatum (F. nucleatum) is an early pathogenic colonizer in periodontitis, but the host response to infection with this pathogen remains unclear. In this study, we built an F. nucleatum infectious model with human periodontal ligament stem cells (PDLSCs) and showed that F. nucleatum could inhibit proliferation, and facilitate apoptosis, ferroptosis, and inflammatory cytokine production in a dose-dependent manner. The F. nucleatum adhesin FadA acted as a proinflammatory virulence factor and increased the expression of interleukin(IL)-1β, IL-6 and IL-8. Further study showed that FadA could bind with PEBP1 to activate the Raf1-MAPK and IKK-NF-κB signaling pathways. Time-course RNA-sequencing analyses showed the cascade of gene activation process in PDLSCs with increasing durations of F. nucleatum infection. NFκB1 and NFκB2 upregulated after 3 h of F. nucleatum-infection, and the inflammatory-related genes in the NF-κB signaling pathway were serially elevated with time. Using computational drug repositioning analysis, we predicted and validated that two potential drugs (piperlongumine and fisetin) could attenuate the negative effects of F. nucleatum-infection. Collectively, this study unveils the potential pathogenic mechanisms of F. nucleatum and the host inflammatory response at the early stage of F. nucleatum infection.

PMID:36754953 | DOI:10.1038/s41368-022-00213-0

Eur J Pharmacol. 2023 Feb 6:175567. doi: 10.1016/j.ejphar.2023.175567. Online ahead of print.

ABSTRACT

INTRODUCTION: Dipyrone has been used as an analgesic for a century, but recently was proposed as a novel therapeutic strategy for the prevention and therapy of pulmonary hypertension (PH). The aim of this study was to analyze whether the risk for ventilation procedures and hospitalization was lower among patients with PH who used dipyrone compared to subjects who did not use dipyrone.

MATERIALS AND METHODS: Initially, patients with PH were retrieved from the TriNetX database, whereby subjects who used dipyrone were assigned to cohort I, and cohort II was formed by those individuals who did not use dipyrone. Both cohorts were matched for several variables. The outcomes were requirement for ventilation procedures and hospital admission, whereby the time window to record events was 5 years after diagnosis of PH. Subsequently, risk analysis was carried out, and risk ratio (RR) and odds ratio (OR) were calculated. In addition, the risk of agranulocytosis was determined for both cohorts.

RESULTS: Out of 741,875 individuals diagnosed with PH 4,282 and 737,593 patients were assigned to the cohorts I and II. After matching, each cohort accounted for 4,278 individuals. Among the cohorts I and II 10 and 187 individuals required ventilation procedures. The according risks of 0.2% vs. 4.4% were significantly different (p < 0.0001; Log-Rank test). RR and OR were 0.053 and 0.051. Within the cohorts I and II 10 and 1,195 subjects required hospital admission. The risks of hospitalization of 0,4% vs. 27.9% differed significantly (p < 0.0001). RR and OR were 0.016 and 0.012. Among the cohorts I and II 47 and 66 individuals were diagnosed with agranulocytosis, whereby no significance was found (p > 0.05).

CONCLUSIONS: The risk for ventilation measures and hospitalization among patients with PH was found to be significantly lower when dipyrone was used. Even though the underlying mechanisms remain unknown to date, they are supposedly mediated by an active metabolite of dipyrone. The obtained results appear to be promising for patients suffering from PH. Hence, the present study may encourage further research.

PMID:36754194 | DOI:10.1016/j.ejphar.2023.175567

Nat Commun. 2023 Feb 7;14(1):668. doi: 10.1038/s41467-023-36306-5.

ABSTRACT

Systemic lupus erythematosus is a heritable autoimmune disease that predominantly affects young women. To improve our understanding of genetic etiology, we conduct multi-ancestry and multi-trait meta-analysis of genome-wide association studies, encompassing 12 systemic lupus erythematosus cohorts from 3 different ancestries and 10 genetically correlated autoimmune diseases, and identify 16 novel loci. We also perform transcriptome-wide association studies, computational drug repurposing analysis, and cell type enrichment analysis. We discover putative drug classes, including a histone deacetylase inhibitor that could be repurposed to treat lupus. We also identify multiple cell types enriched with putative target genes, such as non-classical monocytes and B cells, which may be targeted for future therapeutics. Using this newly assembled result, we further construct polygenic risk score models and demonstrate that integrating polygenic risk score with clinical lab biomarkers improves the diagnostic accuracy of systemic lupus erythematosus using the Vanderbilt BioVU and Michigan Genomics Initiative biobanks.

PMID:36750564 | DOI:10.1038/s41467-023-36306-5

Ther Drug Monit. 2023 Feb 3. doi: 10.1097/FTD.0000000000001082. Online ahead of print.

ABSTRACT

BACKGROUND: Dried blood spot (DBS) sampling is a convenient alternative to whole-blood sampling for therapeutic drug monitoring (TDM) in clinical practice. The aim of this study was to systematically review studies that have examined and used DBS sampling for the TDM of chemotherapy and targeted therapy agents for the treatment of patients with solid cancers.

METHODS: Using the PRISMA guidelines, a systematic literature search of EMBASE and PUBMED was performed to identify eligible clinical studies that used DBS sampling to monitor chemotherapy or targeted therapy for the treatment of solid cancers.

RESULTS: Of the 23 eligible studies, 3 measured concordance between drug concentrations determined by DBS and whole-blood, 7 developed analytical methods of DBS, and 13 performed both. DBS was employed for the TDM of everolimus (3 studies), vemurafenib (2 studies), pazopanib (2 studies), abiraterone (2 studies), mitotane, imatinib, adavosertib, capecitabine, 5-fluorouracil, gemcitabine, cyclophosphamide, ifosfamide, etoposide, irinotecan, docetaxel, gefitinib, palbociclib/ribociclib, and paclitaxel (one study each). The studies included a median of 14 participants (range: 6-34), with 10-50 μL of blood dispensed on DBS cards (20) and Mitra devices (3). Seventeen of the 20 studies that used DBS found no significant impact of the hematocrit on the accuracy and precision of the developed method in the normal hematocrit ranges (eg, 29.0%-59.0%). DBS and plasma or venous concentrations were highly correlated (correlation coefficient, 0.872-0.999) for all drugs, except mitotane, which did not meet a predefined level of significance (r > 0.872; correlation coefficient, r = 0.87, P < 0.0001).

CONCLUSIONS: DBS provides an alternative sampling strategy for the TDM of many anticancer drugs. Further research is required to establish a standardized approach for sampling and processing DBS samples to allow future implementation.

PMID:36750444 | DOI:10.1097/FTD.0000000000001082

medRxiv. 2023 Jan 24:2023.01.18.23284589. doi: 10.1101/2023.01.18.23284589. Preprint.

ABSTRACT

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. This study integrates the latest ALS genome-wide association study (GWAS) summary statistics with functional genomic annotations with the aim of providing mechanistic insights into ALS risk loci, inferring drug repurposing opportunities, and enhancing prediction of ALS risk and clinical characteristics.

METHODS: Genes associated with ALS were identified using GWAS summary statistic methodology including SuSiE SNP-based fine-mapping, and transcriptome- and proteome-wide association study (TWAS/PWAS) analyses. Using several approaches, gene associations were integrated with the DrugTargetor drug-gene interaction database to identify drugs that could be repurposed for the treatment of ALS. Furthermore, ALS gene associations from TWAS were combined with observed blood expression in two external ALS case-control datasets to calculate polytranscriptomic scores and evaluate their utility for prediction of ALS risk and clinical characteristics, including site of onset, age at onset, and survival.

RESULTS: SNP-based fine-mapping, TWAS and PWAS identified 117 genes associated with ALS, with TWAS and PWAS providing novel mechanistic insights. Drug repurposing analyses identified five drugs significantly enriched for interactions with ALS associated genes, with directional analyses highlighting α-glucosidase inhibitors may exacerbate ALS pathology. Additionally, drug class enrichment analysis showed calcium channel blockers may reduce ALS risk. Across the two observed expression target samples, ALS polytranscriptomic scores significantly predicted ALS risk ( R 2 = 4%; p -value = 2.1×10 -21 ).

CONCLUSIONS: Functionally-informed analyses of ALS GWAS summary statistics identified novel mechanistic insights into ALS aetiology, highlighted several therapeutic research avenues, and enabled statistically significant prediction of ALS risk.

PMID:36747854 | PMC:PMC9901068 | DOI:10.1101/2023.01.18.23284589

medRxiv. 2023 Jan 30:2023.01.24.23284960. doi: 10.1101/2023.01.24.23284960. Preprint.

ABSTRACT

Problematic alcohol use (PAU) is a leading cause of death and disability worldwide. To improve our understanding of the genetics of PAU, we conducted a large cross-ancestry meta-analysis of PAU in 1,079,947 individuals. We observed a high degree of cross-ancestral similarity in the genetic architecture of PAU and identified 110 independent risk variants in within- and cross-ancestry analyses. Cross-ancestry fine-mapping improved the identification of likely causal variants. Prioritizing genes through gene expression and/or chromatin interaction in brain tissues identified multiple genes associated with PAU. We identified existing medications for potential pharmacological studies by drug repurposing analysis. Cross-ancestry polygenic risk scores (PRS) showed better performance in independent sample than single-ancestry PRS. Genetic correlations between PAU and other traits were observed in multiple ancestries, with other substance use traits having the highest correlations. The analysis of diverse ancestries contributed significantly to the findings, and fills an important gap in the literature.

PMID:36747741 | PMC:PMC9901058 | DOI:10.1101/2023.01.24.23284960

Front Oncol. 2023 Jan 18;13:1130834. doi: 10.3389/fonc.2023.1130834. eCollection 2023.

NO ABSTRACT

PMID:36741015 | PMC:PMC9890152 | DOI:10.3389/fonc.2023.1130834

Expert Rev Endocrinol Metab. 2023 Feb 5:1-13. doi: 10.1080/17446651.2023.2167709. Online ahead of print.

ABSTRACT

INTRODUCTION: The thionamide anti-thyroid drugs namely carbimazole, methimazole, and propylthiouracil, have been the predominant therapy modality for Graves' hyperthyroidism for over 60 years. Although these agents have proven efficacy and favorable side-effect profiles, non-thionamide alternatives are occasionally indicated in patients who are intolerant or unresponsive to thionamides alone. This review examines the available non-thionamide drug options for the control of Graves' hyperthyroidism and summarizes their clinical utility, efficacy, and limitations.

AREAS COVERED: We reviewed existing literature on mechanisms, therapeutic utility, and side-effect profiles of non-thionamide anti-thyroid drugs. Established non-thionamide agents act on various phases of the synthesis, release, and metabolism of thyroid hormones and comprise historical agents such as iodine compounds and potassium perchlorate as well as drug repurposing candidates like lithium, glucocorticoids, beta-blockers, and cholestyramine. Novel experimental agents in development target key players in Graves' disease pathogenesis including B-cell depletors (Rituximab), CD40 blockers (Iscalimab), TSH-receptor antagonists, blocking antibodies, and immune-modifying peptides.

EXPERT OPINION: Non-thionamide anti-thyroid drugs are useful alternatives in Graves' hyperthyroidism and more clinical trials are needed to establish their safety and long-term efficacy in hyperthyroidism control. Ultimately, the promise for a cure will lie in novel approaches that target the well-established immunopathogenesis of Graves' disease.

PMID:36740774 | DOI:10.1080/17446651.2023.2167709

Int J Biol Macromol. 2023 Feb 3:123540. doi: 10.1016/j.ijbiomac.2023.123540. Online ahead of print.

ABSTRACT

SARS-CoV-2 Main protease (Mpro) is a well-known drug target against SARS-CoV-2 infection. Identification of Mpro inhibitors is vigorously pursued due to its crucial role in viral replication. The present study was aimed to identify Mpro inhibitors via repurposing of US-FDA approved drugs by STD-NMR spectroscopy. In this study, 156 drugs and natural compounds were evaluated against Mpro. Among them, 10 drugs were found to be interacting with Mpro, including diltiazem HCl (1), mefenamic acid (2), losartan potassium (3), mexiletine HCl (4), glaucine HBr (5), trimebutine maleate (6), flurbiprofen (7), amantadine HCl (8), dextromethorphan (9), and lobeline HCl (10) in STD-NMR spectroscopy. Their interactions were compared with three standards (Repurposed anti-viral drugs), dexamethasone, chloroquine phosphate, and remdesivir. Thermal stability of Mpro and dissociation constant (Kd) of six interacting drugs were also determined using DSF. RMSD plots in MD simulation studies showed the formation of stable protein-ligand complexes. They were further examined for their antiviral activity by plaque reduction assay against SARS-CoV-2, which showed 55-100 % reduction in viral plaque. This study demonstrates the importance of drug repurposing against emerging and neglected diseases. This study also exhibits successful application of STD-NMR spectroscopy and plaque reduction assay in rapid identification of potential anti-viral agents.

PMID:36740128 | DOI:10.1016/j.ijbiomac.2023.123540

Bioorg Med Chem Lett. 2023 Feb 3:129171. doi: 10.1016/j.bmcl.2023.129171. Online ahead of print.

ABSTRACT

The use of computational techniques in the early stages of drug discovery has recently experienced a boost, especially in the target identification step. Finding the biological partner(s) for new or existing synthetic and/or natural compounds by "wet" approaches may be challenging; therefore, preliminary in silico screening is even more recommended. This digest, after a brief overview of some of the most known target identification techniques, reviews recent advances in structure-based computational approaches for target identification, focusing on Inverse Virtual Screening and its recent applications. Moreover, future perspectives concerning the use of such methodologies, coupled or not with other approaches, are analyzed.

PMID:36739998 | DOI:10.1016/j.bmcl.2023.129171

J Hepatol. 2023 Feb 2:S0168-8278(23)00072-7. doi: 10.1016/j.jhep.2023.01.019. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Drug-induced liver injury (DILI), both intrinsic and idiosyncratic, causes frequent morbidity, mortality, clinical trial failures and post-approval withdrawal. This suggests an unmet need for improved in vitro models for DILI risk prediction that can account for diverse host genetics and other clinical factors. In this study, we evaluated the utility of human liver organoids (HLOs) for high-throughput DILI risk prediction and in an organ-on-chip system.

METHODS: HLOs were derived from 3 separate iPSC lines and benchmarked on two platforms for their ability to model in vitro liver function and identify hepatotoxic compounds using biochemical assays for albumin, ALT, and AST, microscopy-based morphological profiling, and single-cell transcriptomics: 1) HLOs dispersed in 384-well formatted plates and exposed to a library of compounds. 2) HLOs adapted to a liver-on-chip system.

RESULTS: 1) Dispersed HLOs derived from the 3 iPSC lines had similar DILI predictive capacity to intact HLOs in a high-throughput screening format allowing for measurable IC50 values of compound cytotoxicity. Distinct morphological differences were observed in cells treated with drugs exerting differing mechanisms of toxicity. 2) On-chip HLOs significantly increased albumin production, CYP450 expression, and ALT/AST release when treated with known DILI drugs compared to dispersed HLOs and primary human hepatocytes. On-chip HLOs were able to predict the synergistic hepatotoxicity of tenofovir-inarigivir and showed steatosis and mitochondrial perturbation via phenotypic and transcriptomic analysis with exposure to FIAU and acetaminophen, respectively.

CONCLUSIONS: The high throughput and liver-on-chip system exhibit enhanced in vivo-like function and demonstrate the potential utility of these platforms for hepatotoxicity risk assessment. Tenofovir-inarigivr associated hepatotoxicity was observed and correlates with the clinical manifestation of DILI observed in patients.

PMID:36738840 | DOI:10.1016/j.jhep.2023.01.019

Comput Biol Med. 2023 Jan 24;154:106601. doi: 10.1016/j.compbiomed.2023.106601. Online ahead of print.

ABSTRACT

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most incident reproductive diseases, and remains the main cause of female infertility. Granulosa cells play a critical role in normal follicle development and steroid hormones synthesis. In spite of extensive research, no sole medication has been approved by FDA to treat PCOS. This study aimed to investigate the novel therapeutics targets in PCOS, focusing on granulosa cells transcriptome functional analysis with a drug repositioning approach.

METHODS: PCOS microarray and RNA-Seq datasets in granulosa cells were screened and reanalyzed. KEGG pathway enrichment and interaction network analyses were performed and followed by a set of drug signature screening and Poly-pharmacology survey.

RESULTS: 545 deregulated genes were identified via filters including padj < 0.05 and |log2FC| > 1. Amongst the top 15 KEGG pathways significantly enriched, metabolism of xenobiotics by cytochrome P450, steroid hormone biosynthesis and ovarian steroidogenesis were observed. The Protein-Protein Interaction network identified 18 hub genes amongst this set. Interestingly, most candidate drug signatures have been introduced by databases are either FDA approved or entered into clinical trials, including melatonin, resveratrol and raloxifene. Investigational or experimental introduced drugs obey rules of drug-likeness with almost safe and acceptable ADMET properties. Notably, 21 top target genes of the final drug set were also included in the granulosa significant differentially expressed genes.

CONCLUSION: Results of the current study represent approved, investigational and experimental drug signatures according to the differentially expressed genes in granulosa cells with supported literature reviews. This data might be useful for researchers and clinicians to pave the way for better management of PCOS.

PMID:36738709 | DOI:10.1016/j.compbiomed.2023.106601

Endoscopy. 2023 Dec;55(S 01):E397-E399. doi: 10.1055/a-2008-0087. Epub 2023 Feb 3.

NO ABSTRACT

PMID:36736361 | PMC:PMC9897947 | DOI:10.1055/a-2008-0087

Immunity. 2023 Jan 24:S1074-7613(23)00018-3. doi: 10.1016/j.immuni.2023.01.008. Online ahead of print.

ABSTRACT

Gaucher disease (GD) is the most common lysosomal storage disease caused by recessive mutations in the degrading enzyme of β-glucosylceramide (β-GlcCer). However, it remains unclear how β-GlcCer causes severe neuronopathic symptoms, which are not fully treated by current therapies. We herein found that β-GlcCer accumulating in GD activated microglia through macrophage-inducible C-type lectin (Mincle) to induce phagocytosis of living neurons, which exacerbated Gaucher symptoms. This process was augmented by tumor necrosis factor (TNF) secreted from activated microglia that sensitized neurons for phagocytosis. This characteristic pathology was also observed in human neuronopathic GD. Blockade of these pathways in mice with a combination of FDA-approved drugs, minocycline (microglia activation inhibitor) and etanercept (TNF blocker), effectively protected neurons and ameliorated neuronopathic symptoms. In this study, we propose that limiting unrestrained microglia activation using drug repurposing provides a quickly applicable therapeutic option for fatal neuronopathic GD.

PMID:36736320 | DOI:10.1016/j.immuni.2023.01.008

PLoS One. 2023 Feb 3;18(2):e0281281. doi: 10.1371/journal.pone.0281281. eCollection 2023.

ABSTRACT

Although the COVID-19 pandemic began over three years ago, the virus responsible for the disease, SARS-CoV-2, continues to infect people across the globe. As such, there remains a critical need for development of novel therapeutics against SARS-CoV-2. One technology that has remained relatively unexplored in COVID-19 is the use of antisense oligonucleotides (ASOs)-short single-stranded nucleic acids that bind to target RNA transcripts to modulate their expression. In this study, ASOs targeted against the SARS-CoV-2 genome and host entry factors, ACE2 and TMPRSS2, were designed and tested for their ability to inhibit cellular infection by SARS-CoV-2. Using our previously developed SARS-CoV-2 bioassay platform, we screened 180 total ASOs targeting various regions of the SARS-CoV-2 genome and validated several ASOs that potently blocked SARS-CoV-2 infection in vitro. Notably, select ASOs retained activity against both the WA1 and B.1.1.7 (commonly known as alpha) variants. Screening of ACE2 and TMPRSS2 ASOs showed that targeting of ACE2 also potently prevented infection by the WA1 and B.1.1.7 SARS-CoV-2 viruses in the tested cell lines. Combined with the demonstrated success of ASOs in other disease indications, these results support further research into the development of ASOs targeting SARS-CoV-2 and host entry factors as potential COVID-19 therapeutics.

PMID:36735698 | DOI:10.1371/journal.pone.0281281

Appl Biochem Biotechnol. 2023 Feb 3. doi: 10.1007/s12010-023-04376-2. Online ahead of print.

ABSTRACT

Although there is presently no cure for Parkinson's disease (PD), the available therapies are only able to lessen symptoms and preserve the quality of life. Around 10 million people globally had PD as of 2020. The widely used standard drug has recently been revealed to have several negative effects. Additionally, there is a dearth of innovative compounds entering the market as a result of subpar ADMET characteristics. Drug repurposing provides a chance to reenergize the sluggish drug discovery process by identifying new applications for already-approved medications. As this strategy offers a practical way to speed up the process of developing alternative medications for PD. This study used a computer-aided technique to select therapeutic agent(s) from FDA-approved neuropsychiatric/psychotic drugs that can be adopted in the treatment of Parkinson's disease. In the current work, a computational approach via molecular docking, density functional theory (DFT), and pharmacokinetics were used to identify possible (anti)neuropsychiatric/psychotic medications for the treatment of PD. By using molecular docking, about eight (anti)neuropsychiatric/psychotic medications were tested against PARKIN, a key protein in PD. Based on the docking score, the best ligand in the trial was determined. The top hits were compared to the reference ligand levodopa (L-DOPA). A large proportion of the drugs displayed binding affinity that was relatively higher than L-DOPA. Also, DFT analysis confirms the ligand-receptor interactions and the molecular charge transfer. All the compounds were found to obey Lipinski's rule with acceptable pharmacokinetic properties. The current study has revealed the effectiveness of antineuropsychiatric/antipsychotic drugs against PARKIN in the treatment of PD and lumateperone was revealed to be the most promising candidate interacting with PARKIN.

PMID:36735144 | DOI:10.1007/s12010-023-04376-2