Effects Of Small Molecule Drugs Research Articles

Investigation of Basolateral Targeting Micelles for Drug Delivery Applications in Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease (ADPKD) is a complex disorder characterized by uncontrolled renal cyst growth, leading to kidney function decline. The multifaceted nature of ADPKD suggests that single-pathway interventions using individual small molecule drugs may not be optimally effective. As such, a strategy encompassing combination therapy that addresses multiple ADPKD-associated signaling pathways could offer synergistic therapeutic results. However, severe off-targeting side effects of small molecule drugs pose a major hurdle to their clinical transition. To address this, we identified four drug candidates from ADPKD clinical trials, bardoxolone methyl (Bar), octreotide (Oct), salsalate (Sal), and pravastatin (Pra), and incorporated them into peptide amphiphile micelles containing the RGD peptide (GRGDSP), which binds to the basolateral surface of renal tubules via integrin receptors on the extracellular matrix. We hypothesized that encapsulating drug combinations into RGD micelles would enable targeting to the basolateral side of renal tubules, which is the site of disease, via renal secretion, leading to superior therapeutic benefits compared to free drugs. To test this, we first evaluated the synergistic effect of drug combinations using the 20% inhibitory concentration for each drug (IC20) on renal proximal tubule cells derived from Pkd1flox/-:TSLargeT mice. Next, we synthesized and characterized the RGD micelles encapsulated with drug combinations and measured their in vitro therapeutic effects via a 3D PKD growth model. Upon both IV and IP injections in vivo, RGD micelles showed a significantly higher accumulation in the kidneys compared to NT micelles, and the renal access of RGD micelles was significantly reduced after the inhibition of renal secretion. Specifically, both Bar+Oct and Bar+Sal in the RGD micelle treatment showed enhanced therapeutic efficacy in ADPKD mice (Pkd1fl/fl;Pax8-rtTA;Tet-O-Cre) with a significantly lower KW/BW ratio and cyst index as compared to PBS and free drug-treated controls, while other combinations did not show a significant difference. Hence, we demonstrate that renal targeting through basolateral targeting micelles enhances the therapeutic potential of combination therapy in genetic kidney disease.

Comprehensive analysis of m6A modification patterns and m6A-related lncRNAs as potential biomarkers in lung adenocarcinoma.

N6-methyladenosine (m6A) methylation is considered to induce tumor cell proliferation, migration, and apoptosis. Understanding the mechanism of m6A-related lncRNAs in the development of lung adenocarcinoma (LUAD) may help predict prognosis. m6A-related lncRNAs related to lung cancer were identified and combined with the MeRIP-Seq dataset. The consensus clustering method was utilized to divide LUAD patients, and prognostic model was constructed using the Lasso Cox algorithm. The cluster profiler package was used for gene ontology and KEGG enrichment. The proportion of immune infiltration was estimated using the CIBERSORT algorithm. The decision tree was constructed by the rpart package, and nomograms were built by the rms package. The Connectivity Map database was analyzed for the therapeutic effects of small molecule drugs for LUAD. In addition, qPCR, colony formation and transwell assays were performed to validate functions of m6A-associated lncRNAs. Nineteen m6A-modified lncRNAs in LUAD were identified. LUAD patients were divided into two categories based on the expression of 19 m6A-related lncRNAs. Cluster 2 patients had better antigen production and expression, while naive B cells, plasma cells, and activated NK cells were lower in cluster 1. Nine m6A-related lncRNAs were selected to establish a risk model for evaluating the prognosis of LUAD patients. The high-risk group had higher tumor mutational burden and lower TIDE scores with more gamma delta T cells and neutrophils. Nomograms showed that the prognostic model had predominant predictive ability for LUAD patients based on the risk score analyzed by the decision tree model. Benzo(a)pyrene and neurodazine might improve the prognosis of LUAD patients. The qRT-PCR results confirmed the reliability of the analytical results. The establishment of a prognostic model of m6A-related lncRNAs can independently predict overall survival in LUAD and may help to develop personalized immunotherapy strategies.

Quercetin and Luteolin may be the New Effective Drugs for Radiation Pneumonitis: Based on a Systems Pharmacology

Background: The occurrence of radiation pneumonia not only affects the efficacy of radiotherapy, but also seriously threatens the health of patients undergoing radiotherapy for lung cancer. Studies have suggested that a feining granule is a potentially effective drug for the treatment of radiation pneumonitis, but its mechanism and main components are still unclear. Our study used bioinformatics methods to analyze the main drug Aster tataricus L. f. in feining granules and aims to gain the main mechanism in the treatment of radiation pneumonitis. Methods: Analyzed the effective drug components and targets of A tataricus through the Traditional Chinese Medicine Systems Pharmacology website. And obtained gene targets related to radiation pneumonia through the website of OMIM, Genecard, and Disgenet. Protein–protein interaction (PPI), gene ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the obtained drugs and gene-related targets were conducted. Verify the effects of small molecule drugs on corresponding targets by conducting molecular docking experiments. Results: In total, 193 targets were identified for 13 molecules of A tataricus, and 897 genes were identified to be related to radiation pneumonia. Finally, we obtained 111 genes by crossing drug and disease-related target genes. Using PPI, GO, and KEGG analysis, we found TP53, HSP90AA1, RELA, JUN, AKT1, mitogen-activated protein kinase 1 ( MAPK1), tumor necrosis factor ( TNF), and interleukin-6 ( IL-6) are the most critical genes, which were mainly focused on the GOs of DNA-binding transcription factor, RNA polymerase II-specific DNA-binding transcription factor and protein serine/threonine kinase activity, and the pathways of lipids and atherosclerosis, advanced glycation end products and their receptors, and IL-17. Conclusion: Through molecular docking experiments, it was found that the small molecules of quercetin and luteolin bind tightly to RELA and JUN proteins. We reveal the mechanism of action of A tataricus in the treatment of radiation pneumonia. Quercetin and luteolin may be effective small molecules for radiation pneumonitis.

Novel Techniques for Small Molecule-Based Drug Delivery in Cancerous Tissue: A Literature Review

Introduction: Small molecule cancer drugs target rapidly growing cancerous and healthy cells, leading to negative side effects. Due to the broad effects of small molecule drugs (SMDs), particularly on healthy cells, researchers have established methods such as altering lipophilicity, introducing drug conjugates, and nano-based drug delivery methods to diminish side effects. Methods: Relevant biomedical literature between 1991 to 2021 was obtained using Medline PubMed. Search terms were “physicochemical properties”, “nanotubes”, “liposomes”, and “small molecule drug conjugates”. Literature was selected based on pertinency after assessing the abstracts. Results: Properties such as a drug’s lipophilicity influence most SMD’s promiscuity. Controlling the hydrophobic features of lipophilic drugs within optimal ranges increases their specificity, half-life, and aqueous solubility. However, the narrow optimal range of lipophilicity makes it challenging to observe noticeable effects without reducing therapeutic effects. SMD conjugates improve drug delivery using a targeting ligand, and a therapeutic payload. The targeting ligand ensures greater binding to receptors on target tissues, such that a lower dose of a drug is required, thereby decreasing toxicity. SMD conjugates are non-immunogenic and have lower molecular weights, allowing for greater entry into solid tumours. Several nanomedical approaches have been developed to improve drug delivery. Carbon nanotubes, which exploit the enhanced permeability and retention effect, increase the accumulation of the drug at the cancerous tissue. Another method involves the use of liposomes, which exhibit high biocompatibility with cell membranes, low toxicity, and capability to carry hydrophobic as well as hydrophilic molecules. Discussion: While said novel therapies show increased targeting effects and decreased toxicity, notable limitations exist. Some SMD chemotherapeutics with high lipophilicity has been linked to adverse side effects. Conversely, lower lipophilicity ranges may reduce the permeability and potency of the drug. Alternatively, select SMD conjugates display poorer bioavailability, quick clearance, and multidrug resistance. Moreover, the toxicity of carbon nanotubes is not entirely deduced which may be associated with negative side effects. Conclusion: This systematic review emphasizes the importance of novel drug delivery systems to mitigate the toxic effects of small molecule cancer drugs through changes in lipophilicity, the introduction of drug conjugates, and nano-based drug delivery methods.

Thermal Proteome Profiling in Zebrafish Reveals Effects of Napabucasin on Retinoic Acid Metabolism

AbstractThermal proteome profiling (TPP) allows for the unbiased detection of drug–target protein engagements in vivo. Traditionally, 1 cell type is used for TPP studies, with the risk of missing important differentially expressed target proteins. The use of whole organisms would circumvent this problem. Zebrafish embryos are amenable to such an approach. Here, we used TPP on whole zebrafish embryo lysate to identify protein targets of napabucasin, a compound that may affect signal transducer and activator of transcription 3 (Stat3) signaling through an ill-understood mechanism. In zebrafish embryos, napabucasin induced developmental defects consistent with inhibition of Stat3 signaling. TPP profiling showed no distinct shift in Stat3 upon napabucasin treatment, but effects were detected on the oxidoreductase, Pora, which might explain effects on Stat3 signaling. Interestingly, thermal stability of several aldehyde dehydrogenases was affected. Moreover, napabucasin activated aldehyde dehydrogenase enzymatic activity in vitro. Aldehyde dehydrogenases have crucial roles in retinoic acid metabolism, and functionally, we validated napabucasin-mediated activation of the retinoic acid pathway in zebrafish in vivo. We conclude that TPP profiling in whole zebrafish embryo lysate is feasible and facilitates direct correlation of in vivo effects of small molecule drugs with their protein targets.

The Therapeutic Possibility of EBV-Positive Nasopharyngeal Carcinoma through Targeting Somatostatin Receptors

Nasopharyngeal carcinoma (NPC) is a complex epithelial malignancy caused by both internal and environmental factors. Among them, Epstein–Barr virus (EBV) is a definitive etiological factor. The current therapeutic regimen for NPC is far from ideal and recurrence is commonly seen in patients after conventional radio and/or chemotherapy. We have thereby set out to develop new treatments for this deadly disease. Having analyzed a number of nasopharyngeal tissue and cell samples, we found that the level of somatostatin receptors (SSTRs) was positively correlated with EBV infection. Further, SSTR2 is the dominant SSTR isoform expressed in the EBV-positive (EBV (+)) NPC cells, a potential target for precise delivery of therapeutic agents. Cytotoxic effects of small molecule drugs including ansamitocin P-3 (AP-3), camptothecin and colchicine were subsequently evaluated in NPC cells. We found that AP-3 exhibits its strong anti-NPC activities with the IC50 values being 0.07 nM in EBV (+) NPC C666-1 cells and 0.09 nM in EBV (-) NPC CNE2 cells. In the xenograft animal model, AP-3 further shows inhibitory effects on NPC growth. These findings indicated that AP-3’s activity is not related to EBV in NPC cells. Thus, we proposed that SSTR2- specific delivery of AP-3 via linking AP-3 to somatostatin is likely a viable option to treat the EBV (+) NPC patients.

Repurposing old drugs to fight multidrug resistant cancers.

Overcoming multidrug resistance represents a major challenge for cancer treatment. In the search for new chemotherapeutics to treat malignant diseases, drug repurposing gained a tremendous interest during the past years. Repositioning candidates have often emerged through several stages of clinical drug development, and may even be marketed, thus attracting the attention and interest of pharmaceutical companies as well as regulatory agencies. Typically, drug repositioning has been serendipitous, using undesired side effects of small molecule drugs to exploit new disease indications. As bioinformatics gain increasing popularity as an integral component of drug discovery, more rational approaches are needed. Herein, we show some practical examples of in silico approaches such as pharmacophore modelling, as well as pharmacophore- and docking-based virtual screening for a fast and cost-effective repurposing of small molecule drugs against multidrug resistant cancers. We provide a timely and comprehensive overview of compounds with considerable potential to be repositioned for cancer therapeutics. These drugs are from diverse chemotherapeutic classes. We emphasize the scope and limitations of anthelmintics, antibiotics, antifungals, antivirals, antimalarials, antihypertensives, psychopharmaceuticals and antidiabetics that have shown extensive immunomodulatory, antiproliferative, pro-apoptotic, and antimetastatic potential. These drugs, either used alone or in combination with existing anticancer chemotherapeutics, represent strong candidates to prevent or overcome drug resistance. We particularly focus on outcomes and future perspectives of drug repositioning for the treatment of multidrug resistant tumors and discuss current possibilities and limitations of preclinical and clinical investigations.

Angiotensin-II regulates dosing time-dependent intratumoral accumulation of macromolecular drug formulations via 24-h blood pressure rhythm in tumor-bearing mice

One approach to increasing pharmacotherapy effects is administering drugs at times of day when they are most effective and/or best tolerated. Circadian variation in expression of pharmacokinetics- and pharmacodynamics-related genes was shown to contribute to dosing time-dependent differences in therapeutic effects of small molecule drugs. However, influence of dosing time of day on effects of high molecular weight formulations, such as drugs encapsulated in liposomes, has not been studied in detail. This study demonstrates that blood pressure rhythm affects dosing time-dependent variation in effects of high molecular weight formulations. Systolic blood pressure in sarcoma 180-bearing mice showed significant 24-h oscillation. Intratumoral accumulation of fluorescein isothiocyanate-labeled bovine serum albumin (FITC-BSA), an indicator of tumor vascular permeability, varied with dosing time of day, matching phases of blood pressure circadian rhythm. Furthermore, intratumoral accumulation of liposome-encapsulated oxaliplatin (Lipo-L-OHP) increased with increases in systolic blood pressure. Our findings suggest that circadian blood pressure oscillations may be an important factor to consider in dosing strategies for macromolecular drugs and liposomes in cancer therapy.

Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs.

Drug sensitivity and resistance are conventionally quantified by IC50 or Emax values, but these metrics are highly sensitive to the number of divisions taking place over the course of a response assay. The dependency of IC50 and Emax on division rate creates artefactual correlations between genotype and drug sensitivity while obscuring valuable biological insights and interfering with biomarker discovery. We derive alternative drug response metrics that are insensitive to division number. These are based on estimating the magnitude of drug-induced growth rate inhibition (GR) using endpoint or time-course assays. We show that GR50 and GRmax are superior to conventional metrics for assessing the effects of drugs in dividing cells. Moreover, adopting GR metrics requires only modest changes in experimental protocols. We expect GR metrics to improve the study of cell signaling and growth using drugs, discovery of drug response biomarkers, and identification of drugs effective on specific patient-derived tumor cells.

Fluphenazine·HCl and Epigallocatechin Gallate Modulate the Rate of Formation and Structural Properties of Apolipoprotein C-II Amyloid Fibrils.

Protein misfolding and aggregation, leading to amyloid fibril formation, are characteristic of many devastating and debilitating amyloid diseases. Accordingly, there is significant interest in the mechanisms underlying amyloid fibril formation and identification of possible intervention tools. Small molecule drug compounds approved for human use or for use in phase I-III clinical trials were investigated for their effects on amyloid formation by human apolipoprotein (apo) C-II. Several of these compounds modulated the rate of amyloid formation by apoC-II. Epigallocatechin gallate (EGCG), a green tea catechin, was an effective inhibitor of apoC-II fibril formation, and the antipsychotic drug, fluphenazine·HCl, was a potent activator. Both EGCG and fluphenazine·HCl exerted concentration-dependent effects on the rate of fibril formation, bound to apoC-II fibrils with high affinity, and competitively reduced thioflavin T binding. EGCG significantly altered the size distribution of fibrils, most likely by promoting the lateral association of fibrils and subsequent formation of large aggregates. Fluphenazine·HCl did not significantly alter the size distribution of fibrils, but it may induce the formation of a small population of rod-like fibrils that differ from the characteristic ribbon-like fibrils normally observed for apoC-II. The findings of this study emphasize the effects of small molecule drugs on the kinetics of amyloid fibril formation and their roles in determining fibril structure and aggregate size.

Small-Molecule Binding to DNA under Tension and Twist Studied by Magnetic Tweezers

DNA-binding small molecules are present in the cellular environment and are ubiquitously used in biochemistry and biotechnology. Here, we use single molecule magnetic tweezers experiments to study the effect of small-molecule ligands on DNA mechanical properties.Using the magnetic tweezers ability to control both the applied stretching force and torque, we have systematically characterized the mechanical properties of DNA in the presence of Ethidium Bromide (EtBr), a well-known intercalator, and Netropsin, an anti-microbial drug and known minor groove binder. In addition, we have characterized the interactions of Topotecan, a clinically used anti-tumor drug, with bare DNA.Our results show a lengthening of DNA upon EtBr intercalation to an extension of ∼1.5 times the initial contour length and a decrease in DNA twist by 29 +- 3 degrees per intercalation event, in agreement with previous estimates from bulk experiments. Further effects of intercalation are a stabilization of the double strand under high forces and negative torques and a decrease in both the bending and twisting persistence lengths. In contrast, minor groove binding by Netropsin does not change the contour or persistence length significantly, but increases the twist per base of the DNA.For Topotecan, both intercalative and minor-groove binding have been postulated. Our magnetic tweezers results indicate that drug binding at > 50 micromolar concentrations has consequences qualitatively similar to the changes observed for EtBr, in support of a intercalative binding mode for Topotecan.These results point to important consequences of intercalative ligand binding for DNA torsional behavior, which we characterized at the single-molecule level using magnetic tweezers. Ultimately, such insights can help elucidate the effects of small molecule drugs in the cellular environment and their interference with DNA transcription and replication.