A soft-stiff patterned bioengineering model reveals kinase pathways driving directional cell migration in pulmonary arterial hypertension.

Directional cell migration by pulmonary arterial cells (PACs) is one of the important features of diseases involving arterial remodeling, such as pulmonary arterial hypertension (PAH), a disease that is often characterized by reduced arterial compliance and increased extracellular matrix (ECM) stiffening. However, there are no therapeutics that can halt the directional cell migration of PACs in PAH. The inability to identify drug targets or drugs against the directional cell migration during PAH pathogenesis stems from an incomplete understanding of the process and a lack of effective translational models for screening of candidate small molecules.

-Alkyl Sulfamates as a New Class of nsP2 Cysteine Protease Inhibitors with Broad Spectrum Antialphaviral Activity.

The emergence of mosquito-borne alphaviruses that cause chronic arthritis or encephalitis underscores the urgent need for broad-spectrum antiviral therapeutics. The viral nsP2 cysteine protease, which is essential for alphavirus replication, is a promising antiviral target. Vinyl sulfone-based inhibitors, such as RA-2034, potently inhibit nsP2 protease but suffer from glutathione reactivity and species-dependent systemic clearance catalyzed by glutathione -transferase.

Species-Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with In Vivo Antialphaviral Activity.

RA-0002034 () is a potent covalent inhibitor targeting the nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione -transferase (GST)-catalyzed conjugation.

Chemical arsenal for helicase Hunters: Striking the toughest targets in antiviral research.

Helicases have emerged as promising targets in antiviral drug development but remain largely undrugged. To support the focused development of viral helicase inhibitors we identified, collected, and integrated all chemogenomics data for all helicases annotated in the ChEMBL database. After thoroughly curating and enriching the data with accurate annotations we have created a derivative database of helicase inhibitors which we dubbed Heli-SMACC (Helicase-targeting SMAll Molecule Compound Collection).

Effectiveness of task-oriented circuit training on the motor performance of ischaemic stroke patients: a study protocol for randomised clinical trial.

Stroke is one of the most common causes of disability and death worldwide. With the rapidly growing stroke survivor population, it is crucial to identify an effective method for their healthcare. Recovery from stroke is followed by physiotherapy to promote rehabilitation.

Coastal residency and its association with diagnosed hypertension based on findings from a cross-sectional study in rural Bangladesh.

The high prevalence of hypertension in coastal regions poses a significant public health challenge due to factors such as high salt intake, air pollution, poor diets, limited healthcare access, and increased stress levels. However, disparities in diagnosed hypertension between coastal and non-coastal areas in Bangladesh remain underexplored. This study aims to investigate and address the prevalence of diagnosed hypertension among adults in both regions.

A covalent chemical probe for Chikungunya nsP2 cysteine protease with antialphaviral activity and proteome-wide selectivity.

Chikungunya is a mosquito-borne viral disease that causes fever and severe joint pain for which there is no direct acting drug treatments. Vinyl sulfone SGC-NSP2PRO-1 (3) was identified as a potent inhibitor of the nsP2 cysteine protease (nsP2pro) that reduced viral titer against infectious isolates of Chikungunya and other alphaviruses. The covalent warhead in 3 captured the active site C478 and inactivated nsP2pro with a k/K ratio of 5950 M s.

Structural insights into human brachyury DNA recognition and discovery of progressible binders for cancer therapy.

Brachyury is a transcription factor that plays an essential role in tumour growth of the rare bone cancer chordoma and is implicated in other solid tumours. Brachyury is minimally expressed in healthy tissues, making it a potential therapeutic target. Unfortunately, as a ligandless transcription factor, brachyury has historically been considered undruggable.

Species Dependent Metabolism of a Covalent nsP2 Protease Inhibitor with Anti-alphaviral Activity.

RA-0002034 () is a potent covalent inhibitor targeting the alphavirus nsP2 cysteine protease. The species-dependent pharmacokinetics and metabolism of were investigated to evaluate its therapeutic potential. Pharmacokinetic profiling revealed rapid clearance in mice, predominantly mediated by glutathione -transferase (GST)-catalyzed conjugation.

Medication adherence and blood pressure control in treated hypertensive patients: first follow-up findings from the PREDIcT-HTN study in Northern Bangladesh.

Introduction: Adherence to antihypertensive medication is crucial to control blood pressure (BP) and hypertension management outcomes. In Bangladesh, as in many other countries, poor adherence to medication represents a challenge to effective hypertension management. This study aims to investigate the prevalence and relationship between medication adherence and BP management among hypertensive patients in Bangladesh.

Identification of Inhibitors of virus nsP2 ATPase.

Non-structural protein 2 (nsP2), which plays an essential role in replication of CHIKV, contains a protease, helicase, and methyltransferase-like domain. We executed a simple a screen using malachite green to detect compounds that decreased ATP hydrolysis and tested a library of diverse compounds to find inhibitors of CHIKV nsP2 helicase.

A Covalent Chemical Probe for nsP2 Cysteine Protease with Antialphaviral Activity and Proteome-wide Selectivity.

RA-0003022 () was identified as a high-quality covalent chemical probe for nsP2 cysteine protease (nsP2pro). Isoxazole covalently captured the active site C478 and inactivated the enzyme with a / ratio of 6000 Ms. A negative control analog RA-0025453 () retained the covalent warhead but demonstrated >100-fold decrease in enzyme inhibition.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Antialphavirus Activity.

Despite their widespread impact on human health, there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad-spectrum antiviral activity. Analogs of that varied each of the three regions of the molecule were synthesized to establish structure-activity relationships for the inhibition of (CHIKV) nsP2 protease and viral replication.

Lentil adaptation to drought stress: response, tolerance, and breeding approaches.

Lentil Medik.) is a cool season legume crop that plays vital roles in food and nutritional security, mostly in the least developed countries. Lentil is often cultivated in dry and semi-dry regions, where the primary abiotic factor is drought, which negatively impacts lentil growth and development, resulting in a reduction of yield.

Erratum to "The synergistic effects of organic composts and microelements co-application in enhancing potato productivity in saline soils" [Heliyon 10(12), 30 June 2024, Article e32694].

[This corrects the article DOI: 10.1016/j.heliyon.

Identification of Dihydropyrazolo[1,5-]pyrazin-4(5)-ones as Cyclic Products of β-Amidomethyl Vinyl Sulfone Alphavirus Cysteine Protease Inhibitors.

Optimized syntheses of ()-5-(2-ethoxyphenyl)--(3-(methylsulfonyl)allyl)-1-pyrazole-3-carboxamide (RA-0002034, ), a promising antiviral covalent cysteine protease inhibitor lead, were developed. The syntheses avoid the contamination of with the inactive cyclic dihydropyrazolo[1,5-]pyrazin-4(5)-one , which is formed by the intramolecular aza-Michael reaction of the vinyl sulfone warhead under basic conditions and slowly at pH 7.4 in phosphate buffer.

The synergistic effects of organic composts and microelements co-application in enhancing potato productivity in saline soils.

Soil salinity is a major threat hindering the optimum growth, yield, and nutritional value of potato. The application of organic composts and micronutrients can effectively ameliorate the salinity-deleterious effects on potato growth and productivity. Herein, the combined effect of banana and soybean composts (BCo and SCo) application alongside foliar supplementation of boron (B), selenium (Se), cobalt (Co), and titanium (Ti) were investigated for improving growth, physiology, and agronomical attributes of potato plants grown in saline alluvial soil.

Structure Activity of β-Amidomethyl Vinyl Sulfones as Covalent Inhibitors of nsP2 Cysteine Protease with Anti-alphavirus Activity.

Despite their widespread impact on human health there are no approved drugs for combating alphavirus infections. The heterocyclic β-aminomethyl vinyl sulfone RA-0002034 () is a potent irreversible covalent inhibitor of the alphavirus nsP2 cysteine protease with broad spectrum antiviral activity. Analogs of that varied each of three regions of the molecule were synthesized to establish structure-activity relationships for inhibition of (CHIKV) nsP2 protease and viral replication.

STOPLIGHT: A Hit Scoring Calculator.

We introduce STOPLIGHT, a web portal to assist medicinal chemists in prioritizing hits from screening campaigns and the selection of compounds for optimization. STOPLIGHT incorporates services to assess 6 physiochemical and structural properties, 6 assay liabilities, and 11 pharmacokinetic properties, for any small molecule represented by its SMILES string. We briefly describe each service and illustrate the utility of this portal with a case study.

Discovery of a cell-active chikungunya virus nsP2 protease inhibitor using a covalent fragment-based screening approach.

Unlabelled: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that has been responsible for numerous large-scale outbreaks in the last twenty years. Currently, there are no FDA-approved therapeutics for any alphavirus infection. CHIKV non-structural protein 2 (nsP2), which contains a cysteine protease domain, is essential for viral replication, making it an attractive target for a drug discovery campaign.

Characterization of a Nonselective Opioid Receptor Functional Antagonist: Implications for Development as a Novel Opioid Dependence Medication.

Opioids represent the most extensive category of abused substances in the United States, and the number of fatalities caused by these drugs exceeds those associated with all other drug overdoses combined. The administration of naltrexone, a potent pan-opioid receptor antagonist, to an individual dependent on opioids can trigger opioid withdrawal and induce severe side effects. There is a pressing demand for opioid antagonists free of opioid withdrawal effects.

SGC-CLK-1: A chemical probe for the Cdc2-like kinases CLK1, CLK2, and CLK4.

Small molecule modulators are important tools to study both basic biology and the complex signaling of protein kinases. The cdc2-like kinases (CLK) are a family of four kinases that have garnered recent interest for their involvement in a diverse set of diseases such as neurodegeneration, autoimmunity, and many cancers. Targeted medicinal chemistry around a CLK inhibitor hit identified through screening of a kinase inhibitor set against a large panel of kinases allowed us to identify a potent and selective inhibitor of CLK1, 2, and 4.

Explicating genetic architecture governing nutritional quality in pigmented rice.

Rice is one of the most important staple plant foods that provide a major source of calories and nutrients for tackling the global hunger index especially in developing countries. In terms of nutritional profile, pigmented rice grains are favoured for their nutritional and health benefits. The pigmented rice varieties are rich sources of flavonoids, anthocyanin and proanthocyanidin that can be readily incorporated into diets to help address various lifestyle diseases.

How many kinases are druggable? A review of our current understanding.

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress.