Laboratorio de Investigación y Desarrollo de Bioactivos (LIDEB)

Lipid Nanoparticles with Stiripentol and Cannabidiol Oil: From Rational Optimization to Preclinical Characterization

2026-06-19T20:28:26Z

Articulo Pharmaceutics; vol. 18, no. 4 Background/Objectives: Dravet Syndrome (DS) is a severe form of epilepsy that typically manifests in the first year of life and often requires polytherapy with two or more anti- seizure medications (ASMs) to achieve adequate seizure control. Whereas the combination of stiripentol (STP) and cannabidiol (CBD) has demonstrated clinical efficacy, it presents significant formulation challenges due to the low aqueous solubility and poor oral bioavail- ability of both compounds. Furthermore, the high daily dosages of STP (approximately 50 mg/kg/day or higher) and the oily nature of conventional CBD formulations often hinder patient compliance, as pediatric patients frequently reject these treatments due to unfavorable organoleptic properties. Methods: Nanostructured lipid carriers (NLCs) con- taining STP and CBD suspended in an aqueous medium were developed. The formulation was optimized using Response Surface Methodology (RSM) and subjected to comprehen- sive in vitro and in vivo characterization. Results: The optimized formulation exhibited a mean particle size of 175.3 nm, a polydispersity index (PDI) of 0.232, a zeta potential of −8.35 mV, and an encapsulation efficiency greater than 99% for both drugs. Physico- chemical characterization via atomic force microscopy, differential scanning calorimetry, thermogravimetric analysis, X-ray diffraction, and Fourier transform infrared spectroscopy revealed spherical nanoparticles without aggregation, with the drugs molecularly dis- persed within the lipid matrix. Both STP and CBD showed sustained release profiles and demonstrated oral pharmacokinetic profiles that were comparable or superior to current commercial products. Conclusions: This novel formulation represents a promising thera- peutic alternative for DS, enabling the co-administration of STP and CBD while potentially enhancing CBD bioavailability and treatment adherence in pediatric populations.

Advancing Trypanosoma cruzi N-myristoyltransferase as a drug target for Chagas disease through in silico discovery and biochemical evaluation

2026-06-04T20:42:59Z

Articulo Frontiers in Molecular Biosciences; vol. 12 Introduction: N-myristoylation is a crucial lipid modification that governs protein localization, intracellular trafficking, and function in eukaryotic cells. The enzyme N-myristoyltransferase (NMT), which catalyzes this modification, has emerged as an attractive drug target for parasitic diseases. In this study, we performed a comprehensive biochemical and antiparasitic evaluation of Trypanosoma cruzi NMT (TcNMT), utilizing novel "in silico–identified inhibitors” to assess its potential as a therapeutic agent for Chagas disease.Methods: Recombinant TcNMT was cloned, expressed, and purified for enzymatic characterization. Catalytic activity and substrate affinity were evaluated using a fluorescence-based assay. Four in-silico-selected NMT inhibitors were screened for (i) enzyme inhibition, (ii) cytotoxicity in human cardiomyocytes, and (iii) antiparasitic activity in T. cruzi–infected cardiomyocytes. QUINE and the reference inhibitor DDD85646 were further characterized by calculating selectivity indices. Proteomic profiling of myristoylated proteins was conducted in amastigotes and trypomastigotes following treatment with DDD85646 to identify pathway-level effects.Results: All recombinant TcNMT preparations were catalytically active and displayed high affinity for peptide substrates. Among the screened compounds, QUINE showed moderate antiparasitic efficacy but very low cytotoxicity, yielding a high selectivity index (SI = 28.11). In contrast, DDD85646 exhibited greater antiparasitic potency but substantially higher host-cell toxicity (SI = 4.67). Proteomic analysis of DDD85646-treated parasites revealed downregulation of myristoylated proteins in both life stages, including ARF GTPases and enzymes associated with vesicular trafficking and lipid metabolism. Host cell proteomes remained largely unchanged.Discussion: Biochemical characterization and phenotypic testing support TcNMT as a viable therapeutic target for Chagas disease. QUINE demonstrates the most favorable pharmacological profile, combining antiparasitic activity with excellent selectivity and low host toxicity, making it a strong lead candidate for future drug optimization. Proteomics data indicate that NMT inhibition disrupts critical pathways required for parasite viability yet spares host cellular machinery, reinforcing the mechanistic selectivity of TcNMT targeting. Further studies are warranted to improve potency and evaluate in vivo efficacy.

Cannabidiol combined with GABAergic drugs but not with sodium channel blockers prevents the development of drug-resistance seizures in a preclinical model

2026-04-23T20:24:00Z

Articulo Frontiers in Pharmacology; vol. 16 Drug resistance affects 30% of patients with epilepsy. Cannabidiol (CBD) decreases the expression of drug-resistant seizures in specific syndromes. However, it is unknown if CBD prevents the development of drug-resistant condition in epilepsy. This research was conducted to investigate if subchronic administration of CBD with sodium channel blockers modifies the mortality associated with clonic-tonic seizures and the development of the drug-resistant phenotype induced by subchronic administration of 3-mercaptopropionic acid (3-MP) in rats. These effects were compared with those elicited by antiseizure medications acting on the GABA_A receptors. Male Wistar rats were used to evaluate CBD combined with different antiseizure medications (phenobarbital, diazepam, valproic acid, lamotrigine and oxcarbazepine) during the repetitive administration of 3-MP. The mortality rate and development of drug-resistant seizures were estimated. Computational experiments explored interactions between CBD and sodium channel blockers in the NaV1.7 receptor. Subchronic administration of CBD alone did not modify neither the mortality rate nor the development of drug-resistant seizures. CBD combined with phenobarbital or diazepam reduced the mortality rate and prevalence of drug-resistant seizures. In contrast, coadministration of CBD with valproic acid or lamotrigine did not modify neither the mortality rate nor the expression of drug-resistant seizures. Contrariwise, combining CBD with oxcarbazepine at ED₅₀ increases the incidence of drug-resistant seizures. Computational experiments suggested that CBD acting on NaV1.7 interferes with the action of sodium channel blockers and precludes their inhibitory effects. Our results indicate that repeated administration of CBD with GABAergic antiseizure medications, but not sodium channel blockers, decreases the mortality and prevents the development of the drug-resistant phenotype induced by repeatedly provoked severe seizures.

LIDEB’s Useful Decoys (LUDe): A freely available decoy-generation tool: Benchmarking and scope

2025-12-29T20:34:59Z

Articulo Artificial Intelligence in the Life Sciences; vol. 7 In the field of chemoinformatics, and in particular, when developing models to be applied in virtual screening campaigns, it is essential to run retrospective virtual screening experiments that evaluate the performance of such models in a scenario similar to the real one. That is, the ability to recover a small number of active compounds dispersed among a much larger number of compounds without the desired activity. However, such a retrospective experiment is often limited by the relative scarcity of known inactive compounds against the pharmacological target of interest. In these cases, automatic decoy (putative inactive compound) generation tools are often of great importance. Their basic goal is to generate decoys that are similar enough to the known active compounds to challenge the models, but different enough so that the probability that the decoys modulate the molecular target of interest is small. In this article, we report the latest version of our open-source decoy generation tool LUDe, inspired by the well-known DUD-E but designed to reduce the probability of generating decoys topologically similar to known active compounds. We have carried out a benchmarking exercise against DUD-E through 102 pharmacological targets, using the DOE score and the Doppelganger score as comparison criteria. LUDe decoys obtained better DOE scores across most of the targets, indicating a lower risk of artificial enrichment. The mean Doppelganger score, in contrast, was similar for LUDe and DUD-E decoys, exhibiting a slight improvement for LUDe decoys for most of the targets. Simulation experiments were performed to verify whether the generated decoys are unsuitable to validate ligand-based models. Our results suggest that LUDe decoys are apt to be used to validate and compare machine learning ligand-based screening approaches.

Phytoactive-Loaded Lipid Nanocarriers for Simvastatin Delivery: A Drug Repositioning Strategy Against Lung Cancer

2025-07-16T20:13:09Z

Articulo Pharmaceutics; vol. 17, no. 2 Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9–144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: −4.5 ± 0.7 to −16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy.

Application of machine learning to predict unbound drug bioavailability in the brain

2024-07-01T20:09:47Z

Articulo Frontiers in Drug Discovery; vol. 4 Purpose: Optimizing brain bioavailability is highly relevant for the development of drugs targeting the central nervous system. Several pharmacokinetic parameters have been used for measuring drug bioavailability in the brain. The most biorelevant among them is possibly the unbound brain-to-plasma partition coefficient, Kpuu,brain,ss, which relates unbound brain and plasma drug concentrations under steady-state conditions. In this study, we developed new in silico models to predict Kpuu,brain,ss. Methods: A manually curated 157-compound dataset was compiled from literature and split into training and test sets using a clustering approach. Additional models were trained with a refined dataset generated by removing known P-gp and/or Breast Cancer Resistance Protein substrates from the original dataset. Different supervised machine learning algorithms have been tested, including Support Vector Machine, Gradient Boosting Machine, k-nearest neighbors, classificatory Partial Least Squares, Random Forest, Extreme Gradient Boosting, Deep Learning and Linear Discriminant Analysis. Good practices of predictive Quantitative Structure-Activity Relationships modeling were followed for the development of the models. Results: The best performance in the complete dataset was achieved by extreme gradient boosting, with an accuracy in the test set of 85.1%. A similar estimation of accuracy was observed in a prospective validation experiment, using a small sample of compounds and comparing predicted unbound brain bioavailability with observed experimental data. Conclusion: New in silico models were developed to predict the Kpuu,brain,ss of drug candidates. The dataset used in this study is publicly disclosed, so that the models may be reproduced, refined, or expanded, as a useful tool to assist drug discovery processes.

Clustering of small molecules: new perspectives and their impact on natural product lead discovery

2024-06-18T20:10:46Z

Articulo Frontiers in Natural Products; vol. 3 The clustering of small molecules is of considerable importance for computeraided drug discovery and virtual screening applications. The structure of chemical data in appropriate subspaces of the chemical space is relevant to sample datasets in a representative manner, to generate small libraries with wide or narrow chemical coverage (depending on the specific goals), and to guide the selection of subsets of in silico hits that are submitted for experimental confirmation. In the field of natural products, identifying regions of the chemical space where bioactive compounds congregate and understanding the relationship between biosynthetic gene clusters and the molecular structure of secondary metabolites may have a direct impact on natural product discovery and engineering. Here, we briefly discuss general approximations and available resources for the clustering of small molecules, and how the clustering of small molecules can be boosted by the application of novel clustering approximations, namely subspace clustering and multi-view clustering, which represent opposite philosophies of the clustering paradigm. We present some specific applications of small molecule clustering in the field of natural products, and analyze how a chemogenomic perspective may be particularly embodied in the field of natural products.

Rational design of carbonic anhydrase VII inhibitors: Synthesis of new candidates with the sulfamide scaffold

2024-05-31T20:08:30Z

Objeto de conferencia 8th International Electronic Conference on Medicinal Chemistry (ECMC) (On line, 1-30 November, 2022) Here we present the application of a fully validated molecular docking protocol for the rational selection of the most promising N,N’ -disubstituted sulfamides derivatives to be synthesized as potential new hCAVII inhibitors.

Descubrimiento de nuevos anticonvulsivos que actúan mediante interacciones con canales iónicos

2024-05-11T04:07:16Z

Articulo Anales de la Asociación Química Argentina; vol. 110, no. 2 La epilepsia es una enfermedad caracterizada por la presencia recurrente de convulsiones, con las consecuencias neurobiológicas, cognitivas, psicológicas y sociales que esto implica. Esta patología afecta a más de 50 millones de personas en todo el mundo, lo que la convierte en la segunda enfermedad neurológica más común a nivel global. La gran mayoría de los afectados viven en países de bajos ingresos y como consecuencia, casi el 75% de ellos no reciben un tratamiento adecuado. Aun cuando la farmacoterapia es el tratamiento de primera línea para esta patología, aproximadamente un 30% de los pacientes no responden a las terapias farmacológicas existentes. Este contexto motiva la búsqueda constante de nuevos fármacos anticonvulsivos (FACs) más seguros y mejor tolerados que superen el problema de la farmacorresistencia.

Synthesis and biological evaluation of new antiseizure compounds derived from valproic acid

2024-03-11T16:19:37Z

Articulo Future Medicinal Chemistry; vol. 15, no. 9 This article focuses on the design of new anticonvulsant compounds that combine the chemical structure of valproic acid with other interesting scaffolds with anticonvulsant or anti-inflammatory properties. These compounds protected against in vivo acute seizure models (mice). The results revealed the capacity of combining known scaffolds into a single structure to generate new active compounds with multitarget purposes.

LIDeB Tools: A Latin American resource of freely available, open-source cheminformatics apps

2023-08-29T20:40:12Z

Articulo Artificial Intelligence in the Life Sciences; vol. 2 Cheminformatics is the chemical field that deals with the storage, retrieval, analysis and manipulation of an increasing volume of available chemical data, and it plays a fundamental role in the fields of drug discovery, biology, chemistry, and biochemistry. Open source and freely available cheminformatics tools not only contribute to the generation of public knowledge, but also to reduce the technological gap between high- and low- to middle-income countries. Here, we describe a series of in-house cheminformatics applications developed by our academic drug discovery team, which are freely available on our website (https://lideb.biol.unlp.edu.ar/) as Web Apps and stand-alone versions. These apps include tools for clustering small molecules, decoy generation, druggability assessment, classificatory model evaluation, and data standardization and visualization.

Novel Phenobarbital-Loaded Nanostructured Lipid Carriers for Epilepsy Treatment: From QbD to In Vivo Evaluation

2023-08-26T04:07:02Z

Articulo Frontiers in Chemistry; vol. 10 Pharmacological treatments of central nervous system diseases are always challenging due to the restrictions imposed by the blood–brain barrier: while some drugs can effectively cross it, many others, some antiepileptic drugs among them, display permeability issues to reach the site of action and exert their pharmacological effects. The development of last-generation therapeutic nanosystems capable of enhancing drug biodistribution has gained ground in the past few years. Lipid-based nanoparticles are promising systems aimed to improve or facilitate the passage of drugs through biological barriers, which have demonstrated their effectiveness in various therapeutic fields, without signs of associated toxicity. In the present work, nanostructured lipid carriers (NLCs) containing the antiepileptic drug phenobarbital were designed and optimized by a quality by design approach (QbD). The optimized formulation was characterized by its entrapment efficiency, particle size, polydispersity index, and Z potential. Thermal properties were analyzed by DSC and TGA, and morphology and crystal properties were analyzed by AFM, TEM, and XRD. Drug localization and possible interactions between the drug and the formulation components were evaluated using FTIR. In vitro release kinetic, cytotoxicity on non-tumoral mouse fibroblasts L929, and in vivo anticonvulsant activity in an animal model of acute seizures were studied as well. The optimized formulation resulted in spherical particles with a mean size of ca. 178 nm and 98.2% of entrapment efficiency, physically stable for more than a month. Results obtained from the physicochemical and in vitro release characterization suggested that the drug was incorporated into the lipid matrix losing its crystalline structure after the synthesis process and was then released following a slower kinetic in comparison with the conventional immediate-release formulation. The NLC was non-toxic against the selected cell line and capable of delivering the drug to the site of action in an adequate amount and time for therapeutic effects, with no appreciable neurotoxicity. Therefore, the developed system represents a promising alternative for the treatment of one of the most prevalent neurological diseases, epilepsy.

Antiseizure medication discovery: Recent and future paradigm shifts

2023-08-07T20:07:35Z

Articulo Epilepsia Open; vol. 7, no. S1 Despite the ever-increasing number of available options for the treatment of epilepsies and the remarkable advances on the understanding of their pathophysiology, the proportion of refractory patients has remained approximately unmodified during the last 100 years. How efficient are we translating positive outcomes from basic research to clinical trials and/or the clinical scenario? It is possible that fresh thinking and exploration of new paradigms are required to arrive at truly novel therapeutic solutions, as seemingly proven by recently approved first-in-class antiseizure medications and drug candidates undergoing late clinical trials. Here, the author discusses some approximations in line with the network pharmacology philosophy, which may result in highly innovative (and, hopefully, safer and/or more efficacious) medications for the control of seizures, as embodied with some recent examples in the field, namely tailored multi-target agents and low-affinity ligands.

Drug repurposing screening validated by experimental assays identifies two clinical drugs targeting SARS-CoV-2 main protease

2023-08-29T18:27:33Z

Articulo Frontiers in Drug Discovery; vol. 2 The COVID-19 pandemic prompted several drug repositioning initiatives with the aim to rapidly deliver pharmacological candidates able to reduce SARSCoV- 2 dissemination and mortality. A major issue shared by many of the in silico studies addressing the discovery of compounds or drugs targeting SARS-CoV- 2 molecules is that they lacked experimental validation of the results. Here we present a computer-aided drug-repositioning campaign against the indispensable SARS-CoV-2 main protease (MPro or 3CLPro) that involved the development of ligand-based ensemble models and the experimental testing of a small subset of the identified hits. The search method explored random subspaces of molecular descriptors to obtain linear classifiers. The best models were then combined by selective ensemble learning to improve their predictive power. Both the individual models and the ensembles were validated by retrospective screening, and later used to screen the DrugBank, Drug Repurposing Hub and Sweetlead libraries for potential inhibitors of MPro. From the 4 in silico hits assayed, atpenin and tinostamustine inhibited MPro (IC50 1 μM and 4 μM, respectively) but not the papain-like protease of SARSCoV- 2 (drugs tested at 25 μM). Preliminary kinetic characterization suggests that tinostamustine and atpenin inhibit MPro by an irreversible and acompetitive mechanisms, respectively. Both drugs failed to inhibit the proliferation of SARSCoV- 2 in VERO cells. The virtual screening method reported here may be a powerful tool to further extent the identification of novel MPro inhibitors. Furthermore, the confirmed MPro hits may be subjected to optimization or retrospective search strategies to improve their molecular target and anti-viral potency.

Aplicación de la bioinformática en química medicinal: la búsqueda de nuevos moduladores del receptor GABA-a

2023-03-16T04:34:36Z

Objeto de conferencia XIX Jornadas de Jóvenes Investigadores AUGM (Ciudad del Este, 2011) Introducción. La epilepsia es el principal desorden crónico del sistema nervioso central, afectando a unas 50 millones de personas en el mundo. Uno de los principales mecanismos de acción de los fármacos antiepilépticos es la potenciación de la vía GABAérgica, por prolongación del tiempo de acción del neurotransmisor endógeno GABA o por administración de análogos sintéticos del GABA o fármacos que actúan a nivel de sitios alostéricos del receptor. En el presente trabajo se emprendió la búsqueda racional de moduladores de la vía GABAérgica mediante utilización de herramientas bioinformáticas. Metodología. Se utilizaron BLASTp e InterProScan para buscar proteínas con estructura primaria, secundaria y terciaria similares a las de las subunidades del receptor GABAA. Identificado un receptor homólogo al GABAA, se estudió la conservación de aquellos aminoácidos involucrados en unión a fármacos. Se analizó el conjunto de ligandos conocidos del receptor homólogo en busca de potenciales nuevos moduladores de GABAA. Uno de ellos fue ensayado en un modelo animal agudo de convulsión (ensayo scPTZ en ratones). Resultados. Se encontró una gran similitud estructural entre GABAA y GlyR. Muchos de los aminoácidos de GABAA implicados en unión a fármacos se encuentran conservados o sustituidos conservativamente en GlyR. La revisión bibliográfica indicó que 33 ligandos de GlyR han sido ensayados frente al scPTZ test demostrando actividad anticonvulsiva. Se evaluó el acamprosato de sodio, un ligando de GlyR, en el ensayo scPTZ, demostrando su acción proconvulsivante. Conclusiones. La aplicación de herramientas de la bioinformática permitió identificar un nuevo modulador negativo de la vía GABAérgica, según surge de los resultados en el ensayo scPTZ.

Hybrid inhalable microparticles for dual controlled release of levofloxacin and DNase: physicochemical characterization and in vivo targeted delivery to the lungs

2022-12-29T04:05:10Z

Articulo Journal of Materials Chemistry B; vol. 5, no. 17 Current medical treatments against recurrent pulmonary infections caused by Pseudomonas aeruginosa, such as cystic fibrosis (CF) disorder, involve the administration of inhalable antibiotics. The main challenge is, however, the eradication of microbial biofilms immersed in dense mucus that requires high and recurrent antibiotic doses. Accordingly, the development of novel drug delivery systems capable of providing local and controlled drug release in the lungs is a key factor to improve the therapeutic outcome of such therapeutic molecules. Inhalable hybrid carriers were prepared by co-precipitation of CaCO₃ in the presence of alginate and the resulting microparticles were treated with alginate lyase (AL) in order to modify their porosity and enhance the drug loading. The hybrid microparticles were loaded with DNase (mucolytic agent) and levofloxacin (LV, wide-spectrum antibiotic) in the range of 20–40% for LV and 28–67% for DNase, depending on the AL treatment. In vitro studies demonstrated that microparticles were able to control the DNase release for 24 h, while 30–50% of LV was released in 3 days. The morphological characterization was performed by optical, fluorescence and scanning electron microscopies, showing a narrow size distribution (5 μm). FTIR, XRD, DSC and nitrogen adsorption isotherm studies revealed the presence of the drugs in a non-crystalline state. A microcidal effect of microparticles was found on P. aeruginosa in agar plates and corroborated by Live/Dead kit and TEM observations. Finally, to study whether the microparticles improved the localization of LV in the lungs, in vivo studies were performed by pulmonary administration of microparticles to healthy mice via nebulization and dry powder inhalation, followed by the quantification of LV in lung tissue. The results showed that microparticles loaded with LV delivered the antibiotic at least 3 times more efficiently than free LV. The developed system opens the gateway to new drug delivery systems that may provide enhanced therapeutic solutions against bacterial infections and in particular as a potential tool in CF pathology.

Application of target repositioning and in silico screening to exploit fatty acid binding proteins (FABPs) from Echinococcus multilocularis as possible drug targets

2023-11-08T14:15:35Z

Articulo Journal of Computer-Aided Molecular Design; vol. 34, no. 12 Fatty acid binding proteins (FABPs) are small intracellular proteins that reversibly bind fatty acids and other hydrophobic ligands. In cestodes, due to their inability to synthesise fatty acids and cholesterol de novo, FABPs, together with other lipid binding proteins, have been proposed as essential, involved in the trafficking and delivery of such lipophilic metabolites. Pharmacological agents that modify specific parasite FABP function may provide control of lipid signalling pathways, inflammatory responses and metabolic regulation that could be of crucial importance for the parasite development and survival. Echinococcus multilocularis and Echinococcus granulosus are, respectively, the causative agents of alveolar and cystic echinococcosis (or hydatidosis). These diseases are included in the World Health Organization's list of priority neglected tropical diseases. Here, we explore the potential of FABPs from cestodes as drug targets. To this end, we have applied a target repurposing approach to identify novel inhibitors of Echinococcus spp. FABPs. An ensemble of computational models was developed and applied in a virtual screening campaign of DrugBank library. 21 hits belonging to the applicability domain of the ensemble models were identified, and 3 of the hits were assayed against purified E. multilocularis FABP, experimentally confirming the model's predictions. Noteworthy, this is to our best knowledge the first report on isolation and purification of such four FABP, for which initial structural and functional characterization is reported here.

Trypanosomatid-Caused Conditions: State of the Art of Therapeutics and Potential Applications of Lipid-Based Nanocarriers

2021-09-15T20:06:05Z

Articulo Frontiers in Chemistry; vol. 8 Trypanosomatid-caused conditions (African trypanosomiasis, Chagas disease, and leishmaniasis) are neglected tropical infectious diseases that mainly affect socioeconomically vulnerable populations. The available therapeutics display substantial limitations, among them limited efficacy, safety issues, drug resistance, and, in some cases, inconvenient routes of administration, which made the scenarios with insufficient health infrastructure settings inconvenient. Pharmaceutical nanocarriers may provide solutions to some of these obstacles, improving the efficacy-safety balance and tolerability to therapeutic interventions. Here, we overview the state of the art of therapeutics for trypanosomatid-caused diseases (including approved drugs and drugs undergoing clinical trials) and the literature on nanolipid pharmaceutical carriers encapsulating approved and non-approved drugs for these diseases. Numerous studies have focused on the obtention and preclinical assessment of lipid nanocarriers, particularly those addressing the two currently most challenging trypanosomatid-caused diseases, Chagas disease, and leishmaniasis. In general, in vitro and in vivo studies suggest that delivering the drugs using such type of nanocarriers could improve the efficacy-safety balance, diminishing cytotoxicity and organ toxicity, especially in leishmaniasis. This constitutes a very relevant outcome, as it opens the possibility to extended treatment regimens and improved compliance. Despite these advances, last-generation nanosystems, such as targeted nanocarriers and hybrid systems, have still not been extensively explored in the field of trypanosomatid-caused conditions and represent promising opportunities for future developments. The potential use of nanotechnology in extended, well-tolerated drug regimens is particularly interesting in the light of recent descriptions of quiescent/dormant stages of Leishmania and Trypanosoma cruzi, which have been linked to therapeutic failure.

Editorial: Lipid Nanoparticles as a Novel Strategy to Deliver Bioactive Molecules

2021-09-15T20:06:15Z

Contribucion a revista Frontiers in Chemistry; vol. 9 Lipid nanoparticles are so far among the most successful nanodelivery systems, considering the significant proportion of marketed nanocarriers that correspond to this category. High loading capacity, biocompatibility, and environmentally friendly obtention techniques can be mentioned among their most prominent specific advantages. The current research topic on Lipid Nanoparticles as a Novel Strategy to Deliver Bioactive Molecules encompasses original and review articles on a wide range of lipid nanoparticle-related topics, from encapsulation of gene therapies to novel characterization approaches. The collection of articles also expresses the increasing versatility of these nanosystems, owing to the use of hybrid and functionalized carriers.

Stereoselective Synthesis of Highly Substituted Tetrahydropyrans through an Evans Aldol-Prins Strategy

2021-09-03T20:06:54Z

Articulo The Journal of Organic Chemistry; vol. 83, no. 16 A direct and general method for the synthesis of naturally occurring 2,3,4,5,6-pentasubstituted tetrahydropyrans has been developed, employing β,γ-unsaturated N-acyl oxazolidin-2-ones as key starting materials. The combination of the Evans aldol addition and the Prins cyclization allowed the diastereoselective and efficient generation of the desired oxacycles in two fashions: a one-pot Evans aldol-Prins protocol, in which five new σ bonds and five contiguous stereocenters were straightforwardly generated, and a two-step version, which additionally permitted the isolation of β,γ-unsaturated alcohol precursors bearing an N-acyl oxazolidin-2-one in the α position. From these alcohols were also obtained halogenated pentasubstituted tetrahydropyrans as well as 2,3,4,5-tetrasubstituted tetrahydrofurans, shedding light on the mechanism of the process. Computational studies were consistent with the experimental findings, and this innovative Evans aldol-Prins strategy was performed for the preparation of a battery of more than 30 densely substituted tetrahydropyrans, unprecedentedly fused to a 1,3-oxazinane-2,4-dione ring, both in a racemic fashion and in an enantiomeric fashion. These novel molecules were successfully submitted to several transformations to permit simple access to a variety of differently functionalized tetrahydropyrans. Most of these unique molecules were evaluated for their antimicrobial activity against Gram-positive and Gram-negative bacteria and the yeast Candida albicans, and some structure-activity relationships were established.