Molecular Drug Research Articles

User-friendly and industry-integrated AI for medicinal chemists and pharmaceuticals

Artificial intelligence has brought crucial changes to the whole field of natural sciences. Myriads of machine learning algorithms have been developed to facilitate the work of experimental scientists. Molecular property prediction and drug synthesis planning become routine tasks. Moreover, inverse design of compounds with tunable properties as well as on-the-fly autonomous process optimization and chemical space exploration became possible in silico. Affordable robotic platforms exist able to perform thousands of experiments every day, analyzing the results and tuning the protocols. Despite this, most of these developments get trapped at the stage of code or overlooked, limiting their use by experimental scientists. Meanwhile, visibility and the number of user-friendly tools and technologies available to date is too low to compensate for this fact, rendering the development of novel therapeutic compounds inefficient. In this Review, we set the goal to bridge the gap between modern technologies and experimental scientists to improve drug development efficacy. Here we survey advanced and easy-to-use technologies able to help medical chemists at every stage of their research, including those integrated in technological processes during COVID-19 pandemic motivated by the need for fast yet precise solutions. Moreover, we review how these technologies are integrated by industry and clinics to streamline drug development and production. These technologies already transform the current paradigm of scientific thinking and revolutionize not only medicinal chemistry, but the whole field of natural sciences.

Ultrastable fluorinated copolypeptide nanodroplets of loaded mixed liquids with low vaporization threshold

The expansion of ultrasound molecular imaging applications warrants a reduction in ultrasound contrast agent size and significant advancement in the in vivo stability of shell-stabilized bubbles. The shift from first to second-generation ultrasound contrast agents was marked by an improvement in stability as air was replaced by hydrophobic gases like perfluoropropane and sulfur hexafluoride. Further enhancements may be facilitated by focusing on strategies to retain the encapsulated gas within the ultrasound contrast agent shell despite extreme mechanical deformations. In this study, we developed a novel ultrasound contrast agent with a unique shell structure and a specially-formulated, low-boiling fluorinated liquid interior, resulting in superior stability during repeated and prolonged ultrasound-induced oscillations. Our ultra-stable nanodroplets can withstand sustained in vitro ultrasound exposure with minimal signal attenuation and can induce significant signal enhancement and delay in signal attenuation in the kidney, liver, and tumor tissues during in vivo experiments. Furthermore, encapsulating photosensitizers within these nanodroplets and leveraging photothermal effects could further augment the ultrasound imaging signal and verify its efficacy in tumor therapy. The creation of highly stable nanodroplets opens immense potential to augment the role of ultrasound in molecular imaging, therapy, and drug delivery.

Advancing Drug Delivery with Plant Protein-based Nanoparticles: A Comprehensive Overview

The advancement of nanotechnology has made it possible to deliver small molecular drugs in nano-sized particles to target tissues. In this context, natural biomolecules, such as proteins, have gained significant attention as a safer alternative to synthetic polymers commonly used in nanoparticle production. Plant proteins, in particular, are preferred over animal proteins due to their lower risk of causing allergic reactions. Notable plant proteins include zein, soy protein, and wheat protein (gliadin, gluten). Plant protein nanoparticles can be fabricated using various methods, including emulsion, electrospray, desolvation, and complex coacervation, utilizing plant proteins like zein, gliadin, legumin, and soy protein. This review provides an overview of several plant proteins, their applications as excipients or vehicles in drug delivery, and the methods employed to fabricate plant protein nanoparticles. The review aims to shed light on the utilization of natural proteins as alternative excipients in nanotechnology

Cryomilled electrospun nanofiber mats containing d-mannitol exhibit suitable for aerosol delivery of proteins

Dry powder inhalers (DPIs) are the first choice for inhalation drug development. However, some conventional DPI formulation processes require heating, which may damage high molecular weight drugs such as proteins and nucleic acids. In this study, we propose a novel DPI preparation process that avoids the use of heat. Dry powders were prepared by cryomilling nanofiber mats composed of polyvinyl alcohol, D(−)-mannitol (Man), and α-chymotrypsin (α-Chy) as the model drug using the electrospinning method. The addition of Man conferred high dispersibility and excellent in vitro aerosol performance to the nanofiber mat powder in a very short milling time (less than 0.5 min) as assessed using the Andersen cascade impactor. Powders were classified according to the degree of friability, and among these, nanofiber mats containing 15 % Man and milled for 0.25 min exhibited the highest aerosol performance. Nanofiber mats containing Man milled for less than 0.5 min also exhibited greater α-Chy enzymatic activity than a nebulized α-Chy solution. Furthermore, single inhalation induced no significant lung tissue damage as evidenced by lactate dehydrogenase activity assays of mouse bronchoalveolar lavage fluid. This novel DPI formulation process may facilitate the safe and efficient inhalational delivery of therapeutic proteins.

Modeling mechanisms of chemotherapy-induced peripheral neuropathy and chemotherapy transport using induced pluripotent stem cell-derived sensory neurons

Backgroundand Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment and prevention. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. Here, we investigate molecular mechanisms and drug transport in CIPN. Experimental approachHuman sensory neurons were derived from induced pluripotent stem cells (iPSC-SNs), which were characterized using flow cytometry and immunolabeling. These iPSC-SNs were exposed to different concentrations of the two microtubule-targeting agents, paclitaxel and vincristine, with and without pre-exposure to inhibitors and inducers of efflux transporters. Neuronal networks were quantified via fluorescent staining against sensory neuron markers. Transcriptional effects of the chemotherapeutics were examined using quantitative polymerase chain reactions (qPCR). Key resultsPaclitaxel exposure resulted in axonal retraction and thickening, while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded by ABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded by ABCC1). Modulation of efflux transporters indicate that P-gp and MRP1 play a role in modulating neuronal accumulation and neurotoxicity in preliminary experiments. Conclusionand Implications: iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters may play a role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system, and they may present potential therapeutic targets for CIPN.

Forkhead box O1 in metabolic dysfunction-associated fatty liver disease: molecular mechanisms and drug research.

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disease that progresses from hepatic steatosis to non-alcoholic steatohepatitis, cirrhosis, and liver cancer, posing a huge burden on human health. Existing research has confirmed that forkhead box O1 (FOXO1), as a member of the FOXO transcription factor family, is upregulated in MAFLD. Its activity is closely related to nuclear-cytoplasmic shuttling and various post-translational modifications including phosphorylation, acetylation, and methylation. FOXO1 mediates the progression of MAFLD by regulating glucose metabolism, lipid metabolism, insulin resistance, oxidative stress, hepatic fibrosis, hepatocyte autophagy, apoptosis, and immune inflammation. This article elaborates on the regulatory role of FOXO1 in MAFLD, providing a summary and new insights for the current status of drug research and targeted therapies for MAFLD.

Structural and theoretical exploration of a multi-methoxy chalcone: Synthesis, quantum theory, electrostatics, molecular packing, DFT analysis, and in-silico anti-cancer evaluation

This study explores the pharmacological potential of chalcones through a multidisciplinary approach, including synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations. The synthesized compound, analyzed via single crystal X-ray diffraction, crystallized in the triclinic system (space group P-1) with C–H⋯O interactions stabilizing its structure. Hirshfeld surface analysis confirms these interactions, with H–H contacts dominating (45.1 %). Molecular electrostatics analysis reveals charge distribution, and a 3.10 eV HOMO-LUMO energy gap indicates bioactivity. Molecular docking identifies the compound (3a) showed a maximum Gscore of HTNF-α (−9.81 kcal/mol); Tubulin (−7.96 kcal/mol); COX2 (−7.88 kcal/mol), EGFR (−6.72 kcal/mol), and VEGFR1(-2.50 kcal/mol). Where compound (3c) showed maximum binding at the putative binding site with dock scores for VEGFR2 (−9.24 kcal/mol). This research not only advances molecular science but also holds promise for diverse applications, including drug design. The significance of this study lies in its comprehensive exploration of the pharmacological potential of chalcones using a multidisciplinary approach. Through the integration of synthesis, quantum theory, molecular electrostatics, and density functional theory (DFT) calculations, we have extensively explored the structural and biochemical characteristics of these compounds. This investigation has revealed valuable insights that have the potential to lead to significant advancements in the fields of molecular science and drug design. Moreover, the molecular docking studies shed light on the compound's interaction with various biological targets. The significant binding affinities observed for these targets underscore the potential therapeutic relevance of the synthesized compound in diverse disease conditions.

The Role of Rapid Molecular Tests, Whole-genome Sequencing, and Phenotypic Drug Susceptibility Testing in the Detection and Control of Drug-resistant Tuberculosis

The Role of Rapid Molecular Tests, Whole-genome Sequencing, and Phenotypic Drug Susceptibility Testing in the Detection and Control of Drug-resistant Tuberculosis

Anti-rheumatoid arthritis potential of Acorus calamus L. extract by interleukin-17 inhibition: Molecular insights through an in silico study

Context: Interleukin-17 (IL-17) is a pro-inflammatory cytokine that plays a crucial role in immunity and inflammation. Aims: To evaluate the potential therapeutic effects of two compounds, magnosalicine and neotatarine, derived from the ethanolic extract of Acorus calamus L. rhizome, against IL-17. Methods: Utilizing LC/MS analysis combining molecular docking simulations, drug likeness, ADME and toxicity analysis. This study explored the molecular interactions and binding affinities of identified compounds from A. calamus with crucial residues of IL-17, including Tyr62, Pro63, Ile66, Gln94, Ile96, Leu97, and Leu99. Results: The results revealed that magnosalicine and neotatarine exhibited remarkable binding affinities of -10.16 kcal/mol and -9.53 kcal/mol, respectively, indicating their strong interactions with IL-17. Moreover, both compounds displayed superior binding energies compared to other extract constituents. Interestingly, this study highlighted that all terpenoid compounds from the A. calamus rhizome extract were capable of interacting with these key residues of IL-17, resembling the interactions observed with the natural ligand (RMK) and methotrexate. Meanwhile, the analysis results revealed a safer ADME and toxicity profile for neotatarine compared to magnolalicine. Conclusions: This research unveils the promising potential of neotatarine as candidates for further exploration in therapeutic interventions targeting IL-17-related pathways. These findings shed light on the molecular insights of Acorus calamus L. compounds, providing valuable information for developing novel treatments for IL-17-associated disorders.

A machine learning and drug repurposing approach to target ferroptosis in colorectal cancer stratified by sex and KRAS.

The landscape of sex differences in Colorectal Cancer (CRC) has not been well characterized with respect to the mechanisms of action for oncogenes such as KRAS. However, our recent study showed that tumors from male patients with KRAS mutations have decreased iron-dependent cell death called ferroptosis. Building on these findings, we further examined ferroptosis in CRC, considering both sex of the patient and KRAS mutations, using public databases and our in-house CRC tumor cohort. Through subsampling inference and variable importance analysis (VIMP), we identified significant differences in gene expression between KRAS mutant and wild type tumors from male patients. These genes suppress (e.g., SLC7A11 ) or drive (e.g., SLC1A5 ) ferroptosis, and these findings were further validated with Gaussian mixed models. Furthermore, we explored the prognostic value of ferroptosis regulating genes and discovered sex- and KRAS-specific differences at both the transcriptional and metabolic levels by random survival forest with backward elimination algorithm (RSF-BE). Of note, genes and metabolites involved in arginine synthesis and glutathione metabolism were uniquely associated with prognosis in tumors from males with KRAS mutations. Additionally, drug repurposing is becoming popular due to the high costs, attrition rates, and slow pace of new drug development, offering a way to treat common and rare diseases more efficiently. Furthermore, increasing evidence has shown that ferroptosis inhibition or induction can improve drug sensitivity or overcome chemotherapy drug resistance. Therefore, we investigated the correlation between gene expression, metabolite levels, and drug sensitivity across all CRC primary tumor cell lines using data from the Genomics of Drug Sensitivity in Cancer (GDSC) resource. We observed that ferroptosis suppressor genes such as DHODH , GCH1 , and AIFM2 in KRAS mutant CRC cell lines were resistant to cisplatin and paclitaxel, underscoring why these drugs are not effective for these patients. The comprehensive map generated here provides valuable biological insights for future investigations, and the findings are supported by rigorous analysis of large-scale publicly available data and our in-house cohort. The study also emphasizes the potential application of VIMP, Gaussian mixed models, and RSF-BE models in the multi-omics research community. In conclusion, this comprehensive approach opens doors for leveraging precision molecular feature analysis and drug repurposing possibilities in KRAS mutant CRC.

Multi‐synergistic chemotherapeutic drug assemblies to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics

AbstractThe life‐threatening colorectal cancer exhibits multilevel immunosuppressive characteristics, including low immunogenicity, abnormal cellular metabolism, and acidic immunosuppressive microenvironment. In this work, multi‐synergistic chemotherapeutic drug assemblies are fabricated to activate colorectal cancer immunotherapy by modulating the multilevel immunosuppressive characteristics. Without any drug excipients, the glycolysis inhibitor of lonidamine (LON), indoleamine 2,3‐dioxygenase 1 (IDO‐1) inhibitor of NLG919 (NLG), and the photosensitizer of chlorine e6 could self‐assemble into drug assemblies (LNC) with uniform nano‐size distribution and increased drug stability. Moreover, LNC could also promote cellular uptake and enhance drug penetration to enable efficient drug co‐delivery. Especially, the photodynamic therapy (PDT) of LNC could disrupt tumor cells to release tumor‐associated antigens, thus efficiently suppressing primary tumor growth and improving tumor immunogenicity. Meanwhile, LNC could also reduce the activity of IDO‐1 and attenuate the glycolysis metabolism, thereby reversing the multilevel immunosuppressive characteristics to promote T cell activation. Benefiting from the multi‐synergistic effects, LNC efficiently eradicates the primary tumor growth and also activates systemic antitumor immunity for metastatic tumor inhibition. Such a simple formulation but a multi‐synergistic strategy may accelerate the development of translational nanomedicine for colorectal cancer immunotherapy by using small molecular drug combinations.

Baicalin attenuates aflatoxin B1-induced hepatotoxicity via suppressing c-Jun-N-terminal kinase-mediated cell apoptosis.

Aflatoxin B1 (AFB1) is classified as a Class I carcinogen and common pollutant in human and animal food products. Prolonged exposure to AFB1 can induce hepatocyte apoptosis and lead to hepatotoxicity. Therefore, preventing AFB1-induced hepatotoxicity remains a critical issue and is of great significance. Baicalin, a polyphenolic compound derived from Scutellaria baicalensis Georgi, has a variety of pharmacodynamic activities, such as antiapoptotic and anticancer activities. This study systematically investigated the alleviating effect of baicalin on AFB1-induced hepatotoxicity from the perspective of apoptosis and explored the possible molecular mechanism. In the normal human liver cell line L02, baicalin treatment significantly inhibited AFB1-induced c-Jun-N-terminal Kinase (JNK) activation and cell apoptosis. In addition, the in vitro mechanism study demonstrated that baicalin alleviates AFB1-induced hepatocyte apoptosis through suppressing the translocation of phosphorylated JNK to the nucleus and decreasing the phosphorylated c-Jun/c-Jun ratio and the Bax/Bcl2 ratio. Molecular docking and drug affinity responsive target stability assays demonstrated that baicalin has the potential to target JNK. This study provides a basis for the therapeutic effect of baicalin on hepatocyte apoptosis caused by AFB1, indicating that the development of baicalin and JNK pathway inhibitors has broad application prospects in the prevention of hepatotoxicity, especially hepatocyte apoptosis.

Rare histologic transformation of a CTNNB1 (β-catenin) mutated prostate cancer with aggressive clinical course

BackgroundCatenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking.MethodsWe report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays.ResultsImmunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor.ConclusionsThe reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.

DIPG-39. ONCOHISTONE H3.3K27M-DRIVEN CREB5/ID1 AXIS DICTATES THE MALIGNANT CELL STATES OF DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric cancer characterized by the presence of H3K27M-oncohistones, which drive relentless proliferation and differentiation arrest. This study focuses on the H3.3K27M DIPG subtype and investigates the role of the oncohistone-driven CREB5/ID1 axis in promoting malignancy. METHODS We employed a variety of biological in vitro assays and xenograft mouse models utilizing several H3.3K27M and H3.1K27M DIPG cell lines to evaluate the impact of the studied factors on the growth of DIPGs. Additionally, we employed methodologies in molecular biology, bioinformatics, drug screening, and biochemistry to elucidate the underlying mechanisms of tumorigenesis. RESULTS Through inhibition of ID1, this study explores the induction of cellular differentiation and apoptosis in H3.3K27M DIPG, shedding light on the oncogenic mechanisms at play. The intricate regulation of ID1, linked to CREB5—an oncogenic contributor independent of BMP signaling—is elucidated. The involvement of the SWI/SNF complex as a co-regulator of CREB5 is also examined. Moreover, our findings reveal that H3.3K27M-oncohistone triggers CREB5 overexpression, facilitating the formation of a super-enhancer promoter loop at the CREB5 locus. Disruption of this loop demonstrates potent anti-tumor efficacy in treating DIPG. Additionally, the combination of a compound targeting the CREB5/ID1 axis and a BRG1 inhibitor shows promise for DIPG treatment. CONCLUSIONS This research unveils key molecular pathways specific to the H3.3K27M DIPG subtype, offering valuable insights for potential therapeutic interventions against this lethal pediatric cancer. Inhibiting the CREB5/ID1 axis represents a promising strategy for inducing differentiation and apoptosis in DIPG cells, highlighting the potential for targeted therapies in combating this disease.

Recent Progress of Multifunctional Molecular Probes for Triple-Negative Breast Cancer Theranostics.

Breast cancer (BC) poses a significant threat to women's health, with triple-negative breast cancer (TNBC) representing one of the most challenging and aggressive subtypes due to the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. Traditional TNBC treatments often encounter issues such as low drug efficiency, limited tumor enrichment, and substantial side effects. Therefore, it is crucial to explore novel diagnostic and treatment systems for TNBC. Multifunctional molecular probes (MMPs), which integrate target recognition as well as diagnostic and therapeutic functions, introduce advanced molecular tools for TNBC theranostics. Using an MMP system, molecular drugs can be precisely delivered to the tumor site through a targeted ligand. Real-time dynamic monitoring of drug release achieved using imaging technology allows for the evaluation of drug enrichment at the tumor site. This approach enables accurate drug release, thereby improving the therapeutic effect. Therefore, this review summarizes the recent advancements in MMPs for TNBC theranostics, encompassing the design and synthesis of MMPs as well as their applications in the field of TNBC theranostics.

Bioinspired zwitterionic lysine glycopolymers: Enhancing wound repair through microenvironment modulation for bacterial elimination and optimal immunoregulation

Bacterial infected wounds pose a significant threat to patient survival, necessitating prompt and effective therapeutic intervention. Biomaterials that are responsive to wound microenvironments, possess well-defined structures and are facile to fabricate are favored for fulfilling their mission of efficient wound repair. Drawing inspiration from the immunoregulatory properties of natural zwitterionic capsular polysaccharides (ZPS) and glucomannan (GM) as well as the biogenesis of nitric oxide (NO), this study introduces the zwitterionic lysine glycopolymers (ZLGs), which harmoniously integrate the antibacterial, anti-fouling and immunoregulatory functions into one entity, to effectively promote the healing of infected wounds without addition of any external cytokines or molecular drugs. The ZLGs, exhibiting excellent cytocompatibility, restore sustained NO biogenesis (∼7.1 μM) in wound environment and thus to clean bacteria fast and effectively (12 h clearance rate for S. aureus: 97 %; E. coli: 92 %). Notably, the cell-membrane affinitive ZLGs induce efficient aggregation of mannose receptors and polarize the macrophages to M2 phenotype via the PI3K-Akt/STAT3 pathway, resulting in a synergistic enhanced polarization efficiency increasement of 105 %, as compare to the cumulation of individual building modules. The bioinspired ZLGs accelerate the repair of S. aureus infected wounds in vivo, highlighting the significance of this multi-in-one construction strategy for chronic wound treatment.

Human Immunodeficiency Virus Type-1 Genetic Diversity and Drugs Resistance Mutations among People Living with HIV in Karachi, Pakistan.

The human immunodeficiency virus type-1 epidemic in Pakistan has significantly increased over the last two decades. In Karachi, Pakistan, there is a lack of updated information on the complexity of HIV-1 genetic diversity and the burden of drug resistance mutations (DRMs) that can contribute to ART failure and poor treatment outcomes. This study aimed to determine HIV-1 genetic diversity and identify drug-resistance mutations among people living with HIV in Karachi. A total of 364 HIV-positive individuals, with a median age of 36 years, were enrolled in the study. The HIV-1 partial pol gene was successfully sequenced from 268 individuals. The sequences were used to generate phylogenetic trees to determine clade diversity and also to assess the burden of DRMs. Based on the partial pol sequences, 13 distinct HIV-1 subtypes and recombinant forms were identified. Subtype A1 was the most common clade (40%), followed by CRF02_AG (33.2%). Acquired DRMs were found in 30.6% of the ART-experienced patients, of whom 70.7%, 20.7%, and 8.5% were associated with resistance to NNRTIs, NRTIs, and PIs, respectively. Transmitted DRMs were found in 5.6% of the ART-naïve patients, of whom 93% were associated with resistance against NNRTIs and 7% to PIs. The high prevalence of DRMs in ART-experienced patients poses significant challenges to the long-term benefits and sustainability of the ART program. This study emphasizes the importance of continuous HIV molecular epidemiology and drug resistance surveillance to support evidence-based HIV prevention, precise ART, and targeted AIDS care.

Predictions of biorelevant solubility change during dispersion and digestion of lipid-based formulations

Computational approaches are increasingly explored in development of drug products, including the development of lipid-based formulations (LBFs), to assess their feasibility for achieving adequate oral absorption at an early stage. This study investigated the use of computational pharmaceutics approaches to predict solubility changes of poorly soluble drugs during dispersion and digestion in biorelevant media. Concentrations of 30 poorly water-soluble drugs were determined pre- and post-digestion with in-line UV probes using the MicroDISS Profiler™. Generally, cationic drugs displayed higher drug concentrations post-digestion, whereas for non-ionized drugs there was no discernible trend between drug concentration in dispersed and digested phase. In the case of anionic drugs there tended to be a decrease or no change in the drug concentration post-digestion. Partial least squares modelling was used to identify the molecular descriptors and drug properties which predict changes in solubility ratio in long-chain LBF pre-digestion (R2 of calibration = 0.80, Q2 of validation = 0.64) and post-digestion (R2 of calibration = 0.76, Q2 of validation = 0.72). Furthermore, multiple linear regression equations were developed to facilitate prediction of the solubility ratio pre- and post-digestion. Applying three molecular descriptors (melting point, LogD, and number of aromatic rings) these equations showed good predictivity (pre-digestion R2 = 0.70, and post-digestion R2 = 0.68). The model developed will support a computationally guided LBF strategy for emerging poorly water-soluble drugs by predicting biorelevant solubility changes during dispersion and digestion. This facilitates a more data-informed developability decision making and subsequently facilitates a more efficient use of formulation screening resources.

DNA Framework-Enabled 3D Organization of Antiarrhythmic Drugs for Radiofrequency Catheter Ablation.

Preorganizing molecular drugs within a microenvironment is crucial for the development of efficient and controllable therapeutic systems. Here, the use of tetrahedral DNA framework (TDF) is reported to preorganize antiarrhythmic drugs (herein doxorubicin, Dox) in 3D for catheter ablation, a minimally invasive treatment for fast heartbeats, aiming to address potential complications linked to collateral tissue damage and the post-ablation atrial fibrillation (AF) recurrence resulting from incomplete ablation. Dox preorganization within TDF transforms its random distribution into a confined, regular spatial arrangement governed by DNA. This, combined with the high affinity between Dox and DNA, significantly increases local Dox concentration. The exceptional capacity of TDF for cellular internalization leads to a 5.5-fold increase in intracellular Dox amount within cardiomyocytes, effectively promoting cellular apoptosis. In vivo investigations demonstrate that administering TDF-Dox reduces the recurrence rate of electrical conduction after radiofrequency catheter ablation (RFCA) to 37.5%, compared with the 77.8% recurrence rate in the free Dox-treated group. Notably, the employed Dox dosage exhibits negligible adverse effects in vivo. This study presents a promising treatment paradigm that strengthens the efficacy of catheter ablation and opens a new avenue for reconciling the paradox of ablation efficacy and collateral damage.

Molecular Transmission Network and Drug Resistance in Treatment-Naive HIV-1-Infected Patients in the Liangshan District, China.

This study aimed to investigate the molecular transmission network and drug resistance in treatment-naive HIV-1-infected patients in the Liangshan District, China. The research subjects for this study were HIV-1-infected patients who did not receive any antiretroviral therapy (ART) in the Liangshan District between January 2022 and July 2023. Peripheral venous whole-blood samples were collected from the research subjects. Two milliliters of blood was used for CD4+ T lymphocyte counting detection. Ten milliliters of blood was centrifuged to separate the plasma and blood cells for quantitative detection of HIV-1 RNA and DNA and drug resistance testing of HIV-1. A total of 156 participants were included in this study (88 males and 68 females). The median age of the participants was 37 years. The findings revealed a positive correlation between the HIV-1 DNA and the HIV-1 RNA levels (r = 0.478, p < 0.001). However, a negative correlation was observed between the HIV-1 DNA levels and CD4+ T lymphocyte counts (r = -0.186, p = 0.020). Of the 156 participants, 145 were successfully tested for drug resistance of HIV-1 RNA and HIV-1 DNA simultaneously. Four cases failed the HIV-1 RNA drug resistance testing, and another two failed the HIV-1 DNA drug resistance testing. The most common HIV-1 subtype was the CRF07_BC recombinant. In this study, the overall incidence of transmitted drug resistance (TDR) was 8.33%. The resistance rates of non-nucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) were 7.69% and 0.64%, respectively. In addition, 32 participants were found to have drug-resistant mutations. The primary drug-resistant mutations were K103N, V179D, E157Q, and A128T, mainly against efavirenz (EFV) and nevirapine (NVP) resistance. The drug resistance of HIV-1-infected ART-naive patients in the Liangshan District cannot be ignored. HIV-1 drug resistance testing is recommended before initiating ART.