Pharmacophore Identification and Structure-Activity Relationship Analysis of a Series of Substituted Azaindoles as Inhibitors of .

Human African trypanosomiasis is among the World Health Organization's designated neglected tropical diseases. Repurposing strategies are often employed in academic drug discovery programs due to financial limitations, and in this instance, we used human kinase inhibitor chemotypes to identify substituted 4-aminoazaindoles, exemplified by . Structure-activity and structure-property relationship analysis, informed by cheminformatics, identified as a potent inhibitor of growth.

Establishment of a screening platform based on human coronavirus OC43 for the identification of microbial natural products with antiviral activity.

The COVID-19 pandemic has revealed the lack of effective treatments against betacoronaviruses and the urgent need for new broad-spectrum antivirals. Natural products are a valuable source of bioactive compounds with pharmaceutical potential that may lead to the discovery of new antiviral agents. Specifically, compared to conventional synthetic molecules, microbial natural extracts possess a unique and vast chemical diversity and are amenable to large-scale production.

Corrigendum: Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

[This corrects the article DOI: 10.3389/fmicb.2023.

SimpliPyTEM: An open-source Python library and app to simplify transmission electron microscopy and in situ-TEM image analysis.

Introducing SimpliPyTEM, a Python library and accompanying GUI that simplifies the post-acquisition evaluation of transmission electron microscopy (TEM) images, helping streamline the workflow. After an imaging session, a folder of image and/or video files, typically containing low contrast and large file size 32-bit images, can be quickly processed via SimpliPyTEM into high-quality, high-contrast.jpg images with suitably sized scale bars.

Strasseriolides display in vitro and in vivo activity against trypanosomal parasites and cause morphological and size defects in Trypanosoma cruzi.

Neglected diseases caused by kinetoplastid parasites are a health burden in tropical and subtropical countries. The need to create safe and effective medicines to improve treatment remains a priority. Microbial natural products are a source of chemical diversity that provides a valuable approach for identifying new drug candidates.

A nuclear orthologue of the dNTP triphosphohydrolase SAMHD1 controls dNTP homeostasis and genomic stability in .

Maintenance of dNTPs pools in is dependent on both biosynthetic and degradation pathways that together ensure correct cellular homeostasis throughout the cell cycle which is essential for the preservation of genomic stability. Both the salvage and pathways participate in the provision of pyrimidine dNTPs while purine dNTPs are made available solely through salvage. In order to identify enzymes involved in degradation here we have characterized the role of a trypanosomal SAMHD1 orthologue denominated TbHD82.

Bottom-Up Preparation of Phase-Separated Polymersomes.

A bottom-up approach to fabricating monodisperse, two-component polymersomes that possess phase-separated ("patchy") chemical topology is presented. This approach is compared with already-existing top-down preparation methods for patchy polymer vesicles, such as film rehydration. These findings demonstrate a bottom-up, solvent-switch self-assembly approach that produces a high yield of nanoparticles of the target size, morphology, and surface topology for drug delivery applications, in this case patchy polymersomes of a diameter of ≈50 nm.

Identification of novel anti-amoebic pharmacophores from kinase inhibitor chemotypes.

species, , and are opportunistic pathogens that cause a range of brain, skin, eye, and disseminated diseases in humans and animals. These pathogenic free-living amoebae (pFLA) are commonly misdiagnosed and have sub-optimal treatment regimens which contribute to the extremely high mortality rates (>90%) when they infect the central nervous system. To address the unmet medical need for effective therapeutics, we screened kinase inhibitor chemotypes against three pFLA using phenotypic drug assays involving CellTiter-Glo 2.

Antiparasitic Meroterpenoids Isolated from CF-080171.

is a fungal genus from which a wide range of diverse biologically active compounds have been isolated. A CF-080171 extract was identified to exhibit potent activity against 3D7 and Tulahuen whole parasites in a high-throughput screening (HTS) campaign of microbial extracts from the Fundación MEDINA's collection. Bioassay-guided isolation of the active metabolites from this extract afforded eight new meroterpenoids of varying potencies, namely, memnobotrins C-E (-), a glycosylated isobenzofuranone (), a tricyclic isobenzofuranone (), a tetracyclic benzopyrane (), a tetracyclic isobenzofuranone (), and a pentacyclic isobenzofuranone ().

Characterisation of the Molecular Mechanism of Permeation of the Prodrug Me-5ALA across the Human Using Molecular Dynamics Simulations.

The barrier imposed by the outer layer of the skin, the , creates an almost impermeable environment for exogenous substances. Few lipophilic drugs with low molecular mass can passively diffuse through this layer, highlighting the need to develop methods to enable the delivery of more drugs via the transdermal route. The prodrug approach involves modifying the structure of a drug molecule to enhance its permeability across the skin, but it is often difficult to predict how exactly changes in chemical structure affect permeation.

Caught in Action: Visualizing Dynamic Nanostructures Within Supramolecular Systems Chemistry.

Supramolecular systems chemistry has been an area of active research to develop nanomaterials with life-like functions. Progress in systems chemistry relies on our ability to probe the nanostructure formation in solution. Often visualizing the dynamics of nanostructures which transform over time is a formidable challenge.

Achievement Goals across Persistence-Validation of the Spanish Version of the Motivational Persistence Scale.

Background: An important aspect of achievement goals is the persistence and determination that the person possesses in order to achieve it. Spain does not have an adequate instrument for its measurement. First, this article had the aim of adapt and validate the Motivational Persistence Scale of Constantin et al.

Inosine triphosphate pyrophosphatase from Trypanosoma brucei cleanses cytosolic pools from deaminated nucleotides.

Inosine triphosphate pyrophosphatases (ITPases) are ubiquitous house-cleaning enzymes that specifically recognize deaminated purine nucleotides and catalyze their hydrolytic cleavage. In this work, we have characterized the Trypanosoma brucei ITPase ortholog (TbITPA). Recombinant TbITPA efficiently hydrolyzes (deoxy)ITP and XTP nucleotides into their respective monophosphate form.

Syndapin-2 mediated transcytosis of amyloid-β across the blood-brain barrier.

A deficient transport of amyloid-β across the blood-brain barrier, and its diminished clearance from the brain, contribute to neurodegenerative and vascular pathologies, such as Alzheimer's disease and cerebral amyloid angiopathy, respectively. At the blood-brain barrier, amyloid-β efflux transport is associated with the low-density lipoprotein receptor-related protein 1. However, the precise mechanisms governing amyloid-β transport across the blood-brain barrier, in health and disease, remain to be fully understood.

Preclinical evaluation of strasseriolides A-D, potent antiplasmodial macrolides isolated from Strasseria geniculata CF-247,251.

Background: Malaria is a global health problem for which novel therapeutic compounds are needed. To this end, a recently published novel family of antiplasmodial macrolides, strasseriolides A-D, was herein subjected to in vivo efficacy studies and preclinical evaluation in order to identify the most promising candidate(s) for further development.

Methods: Preclinical evaluation of strasseriolides A-D was performed by MTT-based cytotoxicity assay in THLE-2 (CRL-2706) liver cells, cardiotoxicity screening using the FluxOR™ potassium assay in hERG expressed HEK cells, LC-MS-based analysis of drug-drug interaction involving CYP3A4, CYP2D6 and CYP2C9 isoforms inhibition and metabolic stability assays in human liver microsomes.

One-Pot Synthesis of Oxidation-Sensitive Supramolecular Gels and Vesicles.

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles.

The spatiotemporal control of expert tennis players when returning first serves: A perception-action perspective.

The aim of the current experiment was to examine the spatiotemporal control of expert tennis players while executing first service returns within a representative experimental setting. We recruited and tested 12 male expert tennis players in hard courts. A comprehensive analysis of the timing (eleven temporal variables analysed at 300 Hz) and performance success of the return actions were carried out, while simultaneously considering task constraints such as the accuracy and the speed of the serves.

Lead Optimization of 3,5-Disubstituted-7-Azaindoles for the Treatment of Human African Trypanosomiasis.

Neglected tropical diseases such as human African trypanosomiasis (HAT) are prevalent primarily in tropical climates and among populations living in poverty. Historically, the lack of economic incentive to develop new treatments for these diseases has meant that existing therapeutics have serious shortcomings in terms of safety, efficacy, and administration, and better therapeutics are needed. We now report a series of 3,5-disubstituted-7-azaindoles identified as growth inhibitors of , the parasite that causes HAT, through a high-throughput screen.

Structure-property studies of an imidazoquinoline chemotype with antitrypanosomal activity.

Human African trypanosomiasis is a neglected tropical disease (NTD) that is fatal if left untreated. Although approximately 13 million people live in moderate- to high-risk areas for infection, current treatments are plagued by problems with safety, efficacy, and emerging resistance. In an effort to fill the drug development pipeline for HAT, we have expanded previous work exploring the chemotype represented by the compound , with a particular focus on improvement of absorption, distribution, metabolism and elimination (ADME) properties.

A Mitochondrial Orthologue of the dNTP Triphosphohydrolase SAMHD1 Is Essential and Controls Pyrimidine Homeostasis in .

The maintenance of deoxyribonucleotide triphosphate (dNTP) homeostasis through synthesis and degradation is critical for accurate genomic and mitochondrial DNA replication fidelity. makes use of both the salvage and pathways for the provision of pyrimidine dNTPs. In this respect, the sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) appears to be the most relevant dNTPase controlling dNTP/deoxynucleoside homeostasis in mammalian cells.

How Enaction and Ecological Approaches Can Contribute to Sports and Skill Learning.

The purpose of this paper is to explain learning in sports and physical education (PE) from the perspective of enactive and ecological psychology. The learning process is first presented from the enactive perspective, and some relevant notions such as sense-making and sensorimotor schemes are developed. Then, natural learning environments are described, and their importance in the human development process is explained.

A Cyclometalated Iridium (III) Complex as a Microtubule Probe for Correlative Super-Resolution Fluorescence and Electron Microscopy.

The visualization of microtubules by combining optical and electron microscopy techniques provides valuable information to understand correlated intracellular activities. However, the lack of appropriate probes to bridge both microscopic resolutions restricts the areas and structures that can be comprehended within such highly assembled structures. Here, a versatile cyclometalated iridium (III) complex is designed that achieves synchronous fluorescence-electron microscopy correlation.

Strasseriolides A-D, A Family of Antiplasmodial Macrolides Isolated from the Fungus CF-247251.

A novel family of four potent antimalarial macrolides, strasseriolides A-D (-), has been isolated from cultures of CF-247251, a fungal strain obtained from plant tissues. The structures of these compounds, including their absolute configurations, were elucidated by HRMS, NMR spectroscopy, and X-ray single-crystal diffraction. The four compounds gave respective IC values of 9.

Molecular Dynamics Simulation of Small Molecules Interacting with Biological Membranes.

Cell membranes protect and compartmentalise cells and their organelles. The semi-permeable nature of these membranes controls the exchange of solutes across their structure. Characterising the interaction of small molecules with biological membranes is critical to understanding of physiological processes, drug action and permeation, and many biotechnological applications.