Broad inhibition of plasmodium falciparum cytoadherence by (+)-epigallocatechin gallate

<p>Abstract</p> <p>Background</p> <p>The surface antigen P<it>f</it>EMP-1 is a key virulence factor of the human malaria parasite implicated in the cytoadherence of <it>Plasmodium falciparum </it>infected erythrocytes to a range of receptors on host endothelium. Among these host receptors, binding to ICAM-1 is related to cerebral malaria. The majority of the mortality in children with cerebral malaria is seen within 24 h of hospital admission despite the use of effective anti-parasite drugs, therefore, the development of adjunctive therapies is urgently needed.</p> <p>The polyphenolic compound (+)-epigallocatechin gallate ((+)-EGCG) has been previously evaluated for anti-adhesive properties using a small number of laboratory parasite isolates. Here, this property is further explored using a new panel of ICAM-1-binding patient isolates of <it>P. falciparum </it>to ascertain if (+)-EGCG might be effective as a broad spectrum inhibitor of ICAM-1-based cytoadherence.</p> <p>Methods</p> <p><it>Plasmodium falciparum </it>lines, including A4 and ItG as positive controls and nine new ICAM-1 binding patient isolates, were allowed to bind with ICAM-1-Fc protein under static assay conditions in the presence and absence of 50 μM (+)-EGCG. Adhesion levels of all the parasite strains were quantified by microscopy as the mean number of infected erythrocyte (IE) bound per mm²of surface area and statistical comparisons were made to demonstrate the effect of (+)-EGCG on the binding of various parasite variants to human ICAM-1.</p> <p>Results</p> <p>This study revealed that binding of patient isolates to ICAM-1 was reduced significantly with inhibition levels of 37% in patient isolate BC-12 up to a maximum of 80% in patient isolate 8146 at 50 μM (+)-EGCG.</p> <p>Conclusion</p> <p>Evaluation of the anti-adhesive property of (+)-EGCG against a new panel of ICAM-1-binding patient isolates of <it>P. falciparum </it>showed that this inhibitor, identified as potential mimic of the L43 loop of human ICAM-1, was effective at blocking cytoadherence.</p

Computer-driven development of an in silico tool for finding selective histone deacetylase 1 inhibitors

Histone deacetylases (HDACs) are a class of epigenetic modulators overexpressed in numerous types of cancers. Consequently, HDAC inhibitors (HDACIs) have emerged as promising antineoplastic agents. Unfortunately, the most developed HDACIs suffer from poor selectivity towards a specific isoform, limiting their clinical applicability. Among the isoforms, HDAC1 represents a crucial target for designing selective HDACIs, being aberrantly expressed in several malignancies. Accordingly, the development of a predictive in silico tool employing a large set of HDACIs (aminophenylbenzamide derivatives) is herein presented for the first time. Software Phase was used to derive a 3D-QSAR model, employing as alignment rule a common-features pharmacophore built on 20 highly active/selective HDAC1 inhibitors. The 3D-QSAR model was generated using 370 benzamide-based HDACIs, which yielded an excellent correlation coefficient value (R2 = 0.958) and a satisfactory predictive power (Q2 = 0.822; Q2F3 = 0.894). The model was validated (r2ext_ts = 0.794) using an external test set (113 compounds not used for generating the model), and by employing a decoys set and the receiver-operating characteristic (ROC) curve analysis, evaluating the Güner-Henry score (GH) and the enrichment factor (EF). The results confirmed a satisfactory predictive power of the 3D-QSAR model. This latter represents a useful filtering tool for screening large chemical databases, finding novel derivatives with improved HDAC1 inhibitory activity

The green chemistry of chalcones: Valuable sources of privileged core structures for drug discovery

The sustainable use of resources is essential in all production areas, including pharmaceuticals. However, the aspect of sustainability needs to be taken into consideration not only in the production phase, but during the whole medicinal chemistry drug discovery trajectory. The continuous progress in the fields of green chemistry and the use of artificial intelligence are contributing to the speed and effectiveness of a more sustainable drug discovery pipeline. In this light, here we review the most recent sustainable and green synthetic approaches used for the preparation and derivatization of chalcones, an important class of privileged structures and building blocks used for the preparation of new biologically active compounds with a broad spectrum of potential therapeutic applications. The literature here reported has been retrieved from the SciFinder database using the term "chalcone " as a keyword and filtering the results applying the concept: "green chemistry ", and from the Reaxys database using the keywords "chalcone " and "green ". For both databases the time-frame was 2017-2022. References were manually selected based on relevance

Novel Labdane Diterpenes-Based Synthetic Derivatives: Identification of a Bifunctional Vasodilator That Inhibits CaV1.2 and Stimulates KCa1.1 Channels

Sesquiterpenes such as leucodin and the labdane-type diterpene manool are natural compounds endowed with remarkably in vitro vasorelaxant and in vivo hypotensive activities. Given their structural similarity with the sesquiterpene lactone (+)-sclareolide, this molecule was selected as a scaffold to develop novel vasoactive agents. Functional, electrophysiology, and molecular dynamics studies were performed. The opening of the five-member lactone ring in the (+)-sclareolide provided a series of labdane-based small molecules, promoting a significant in vitro vasorelaxant effect. Electrophysiology data identified 7 as a Ca(V)1.2 channel blocker and a K(Ca)1.1 channel stimulator. These activities were also confirmed in the intact vascular tissue. The significant antagonism caused by the Ca(V)1.2 channel agonist Bay K 8644 suggested that 7 might interact with the dihydropyridine binding site. Docking and molecular dynamic simulations provided the molecular basis of the Ca(V)1.2 channel blockade and K(Ca)1.1 channel stimulation produced by 7. Finally, 7 reduced coronary perfusion pressure and heart rate, while prolonging conduction and refractoriness of the atrioventricular node, likely because of its Ca2+ antagonism. Taken together, these data indicate that the labdane scaffold represents a valuable starting point for the development of new vasorelaxant agents endowed with negative chronotropic properties and targeting key pathways involved in the pathophysiology of hypertension and ischemic cardiomyopathy. © 2022 by the authors

Selective Histone Deacetylase 6 Inhibitors Restore Cone Photoreceptor Vision or Outer Segment Morphology in Zebrafish and Mouse Models of Retinal Blindness.

Blindness arising from retinal or macular degeneration results in significant social, health and economic burden. While approved treatments exist for neovascular ('wet') age-related macular degeneration, new therapeutic targets/interventions are needed for the more prevalent atrophic ('dry') form of age-related macular degeneration. Similarly, in inherited retinal diseases, most patients have no access to an effective treatment. Although macular and retinal degenerations are genetically and clinically distinct, common pathological hallmarks can include photoreceptor degeneration, retinal pigment epithelium atrophy, oxidative stress, hypoxia and defective autophagy. Here, we evaluated the potential of selective histone deacetylase 6 inhibitors to preserve retinal morphology or restore vision in zebrafish atp6v0e1 -/- and mouse rd10 models. Histone deacetylase 6 inhibitor, tubastatin A-treated atp6v0e1 -/- zebrafish show marked improvement in photoreceptor outer segment area (44.7%, p = 0.027) and significant improvement in vision (8-fold, p ≤ 0.0001). Tubastatin A-treated rd10/rd10 retinal explants show a significantly (p = 0.016) increased number of outer-segment labeled cone photoreceptors. In vitro, ATP6V0E1 regulated HIF-1α activity, but significant regulation of HIF-1α by histone deacetylase 6 inhibition in the retina was not detected. Proteomic profiling identified ubiquitin-proteasome, phototransduction, metabolism and phagosome as pathways, whose altered expression correlated with histone deacetylase 6 inhibitor mediated restoration of vision

Identification of Novel 3-Hydroxy-pyran-4-One Derivatives as Potent HIV-1 Integrase Inhibitors Using in silico Structure-Based Combinatorial Library Design Approach

We describe herein the development and experimental validation of a computational protocol for optimizing a series of 3-hydroxy-pyran-4-one derivatives as HIV integrase inhibitors (HIV INIs). Starting from a previously developed micromolar inhibitors of HIV integrase (HIV IN), we performed an in-depth investigation based on an in silico structure-based combinatorial library designing approach. This method allowed us to combine a combinatorial library design and side chain hopping with Quantum Polarized Ligand Docking (QPLD) studies and Molecular Dynamics (MD) simulation. The combinatorial library design allowed the identification of the best decorations for our promising scaffold. The resulting compounds were assessed by the mentioned QPLD methodology using a homology model of full-length binary HIV IN/DNA for retrieving the best performing compounds acting as HIV INIs. Along with the prediction of physico-chemical properties, we were able to select a limited number of drug-like compounds potentially displaying potent HIV IN inhibition. From this final set, based on the synthetic accessibility, we further shortlisted three representative compounds for the synthesis. The compounds were experimentally assessed in vitro for evaluating overall HIV-1 IN inhibition, HIV-1 IN strand transfer activity inhibition, HIV-1 activity inhibition and cellular toxicity. Gratifyingly, all of them showed relevant inhibitory activity in the in vitro tests along with no toxicity. Among them HPCAR-28 represents the most promising compound as potential anti-HIV agent, showing inhibitory activity against HIV IN in the low nanomolar range, comparable to that found for Raltegravir, and relevant potency in inhibiting HIV-1 replication and HIV-1 IN strand transfer activity. In summary, our results outline HPCAR-28 as a useful optimized hit for the potential treatment of HIV-1 infection by targeting HIV IN

The FAAH inhibitor URB597 suppresses hippocampal maximal dentate afterdischarges and restores seizure-induced impairment of short and long-term synaptic plasticity

Synthetic cannabinoids and phytocannabinoids have been shown to suppress seizures both in humans and experimental models of epilepsy. However, they generally have a detrimental effect on memory and memory-related processes. Here we compared the effect of the inhibition of the endocannabinoid (eCB) degradation versus synthetic CB agonist on limbic seizures induced by maximal dentate activation (MDA) acute kindling. Moreover, we investigated the dentate gyrus (DG) granule cell reactivity and synaptic plasticity in naïve and in MDA-kindled anaesthetised rats. We found that both the fatty acid amide hydrolase (FAAH) inhibitor URB597 and the synthetic cannabinoid agonist WIN55,212-2 displayed AM251-sensitive anti-seizure effects. WIN55,212-2, dose-dependently (0.5–2 mg/kg, i.p.) impaired short-term plasticity (STP) and long-term potentiation (LTP) at perforant path-DG synapses in naïve rats. Strikingly, URB597 (1 mg/kg, i.p.) was devoid of any deleterious effects in normal conditions, while it prevented seizure-induced alterations of both STP and LTP. Our evidence indicates that boosting the eCB tone rather than general CB1 activation might represent a potential strategy for the development of a new class of drugs for treatment of both seizures and comorbid memory impairments associated with epilepsy.peer-reviewe

Development of a multiplexed activity-based protein profiling assay to evaluate activity of endocannabinoid hydrolase inhibitors

Endocannabinoids, an important class of signaling lipids involved in health and disease, are predominantly synthesized and metabolized by enzymes of the serine hydrolase superfamily. Activity-based protein profiling (ABPP) using fluorescent probes, such as fluorophosphonate (FP)-TAMRA and β-lactone-based MB064, enables drug discovery activities for serine hydrolases. FP TAMRA and MB064 have distinct, albeit partially overlapping, target profiles, but cannot be used in conjunction due to overlapping excitation/emission spectra. We therefore synthesized a novel FP-probe with a green BODIPY as fluorescent tag and studied its labeling profile in mouse proteomes. Surprisingly, we found that the reporter tag plays an important role in the binding potency and selectivity of the probe. A multiplexed ABPP-assay was developed in which a probe cocktail of FP-BODIPY and MB064 visualized most endocannabinoid serine hydrolases in mouse brain proteomes in a single experiment. The multiplexed ABPP-assay was employed to profile endocannabinoid hydrolase inhibitor activity and selectivity in mouse brain

Extra virgin olive oil extracts of indigenous Southern Tuscany cultivar act as anti-inflammatory and vasorelaxant nutraceuticals

Extra virgin olive oil (EVOO) is the typical source of fats in the Mediterranean diet. While fatty acids are essential for the EVOO nutraceutical properties, multiple biological activities are also due to the presence of polyphenols. In this work, autochthonous Tuscany EVOOs were chemically characterized and selected EVOO samples were extracted to obtain hydroalcoholic phytocomplexes, which were assayed to establish their anti-inflammatory and vasorelaxant properties. The polar extracts were characterized via 1H-NMR and UHPLC-HRMS to investigate the chemical composition and assayed in CaCo-2 cells exposed to glucose oxidase or rat aorta rings contracted by phenylephrine. Apigenin and luteolin were found as representative flavones; other components were pinoresinol, ligstroside, and oleuropein. The extracts showed anti-inflammatory and antioxidant properties via modulation of NF-κB and Nrf2 pathways, respectively, and good vasorelaxant activity, both in the presence and absence of an intact endothelium. In conclusion, this study evaluated the nutraceutical properties of autochthonous Tuscany EVOO cv., which showed promising anti-inflammatory and vasorelaxant effects

Nutritionally enriched tomatoes (Solanum lycopersicum L.) grown with wood distillate: chemical and biological characterization for quality assessment

: Bio-based products are nowadays useful tools able to affect the productivity and quality of conventionally cultivated crops. Several bio-based products are currently on the market; one of the newest and most promising is the wood distillate (WD) derived from the pyrolysis process of waste biomass after timber. Its foliar application has been widely investigated and shown to promote the antioxidant profile of cultivated crops. WD was used here as additive for the cultivation of tomato (Solanum lycopersicum L.) plants. The application improved quality (chemical) parameters, minerals, polyphenols, and lycopene contents of tomato fruits. The extracts of WD-treated and untreated tomatoes have been chemically and biologically characterized. The 1 H-NMR and ESI-mass spectrometry analyses of the extracts revealed the presence of different fatty acids, amino acids and sugars. In particular, the WD-treated tomatoes showed the presence of pyroglutamic acid and phloridzin derivatives, but also dihydrokaempferol, naringenin glucoside, cinnamic acid, and kaempferol-3-O-glucoside. When tested in cells, the extracts showed a promising anti-inflammatory profile in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Furthermore, the extracts displayed a slight vasorelaxant activity on rat aorta rings (either endothelium-denuded or endothelium-intact) pre-contracted with phenylephrine or potassium chloride. PRACTICAL APPLICATION: Wood distillate has been used for tomato plant growth. Tomatoes showed improved nutritional parameters, and their extracts displayed antioxidant and anti-inflammatory activities