Strategies against nonsense: oxadiazoles as translational readthrough-inducing drugs (TRIDs)

This review focuses on the use of oxadiazoles as translational readthrough-inducing drugs (TRIDs) to rescue the functional full-length protein expression in mendelian genetic diseases caused by nonsense mutations. These mutations in specific genes generate premature termination codons (PTCs) responsible for the translation of truncated proteins. After a brief introduction on nonsense mutations and their pathological effects, the features of various classes of TRIDs will be described discussing differences or similarities in their mechanisms of action. Strategies to correct the PTCs will be presented, particularly focusing on a new class of Ataluren-like oxadiazole derivatives in comparison to aminoglycosides. Additionally, recent results on the efficiency of new candidate TRIDs in restoring the production of the cystic fibrosis transmembrane regulator (CFTR) protein will be presented. Finally, a prospectus on complementary strategies to enhance the effect of TRIDs will be illustrated together with a conclusive paragraph about perspectives, opportunities, and caveats in developing small molecules as TRIDs

In vitro and in silico studies of polycondensed diazine systems as anti-parasitic agents

Parasitic diseases caused by protozoarian agents are still relevant today more than ever. Recently, we synthesized several polycondensed diazine derivatives by means 1,3-dipolar cycloaddition reactions. A broad selection of these compounds were submitted to in vitro biological screening against Plasmodium falciparum, Leishmania infantum, Trypanosoma brucei, and Trypanosoma cruzi, resulting active at micromolar level. Induced Fit Docking/MM-GBSA studies were performed giving interesting indications about the probable mechanism of action of the most active compound

Rilevamento delle sorgenti doppler della ionosfera tramite radar-HF

Il presente lavoro contiene un insieme di concetti di base utili per comprendere la cosiddetta tecnica della “interferometria doppler”, usata, nell’ambito degli studi sulla ionosfera, per ricavare informazioni sulla conformazione e velocità degli strati riflettenti (operazione chiamata anche sky mapping). È utile ricordare, infatti, che il sondaggio ionosferico tradizionale consente solo la determinazione dell’altezza virtuale di ogni strato, pensato come un unico oggetto riflettente piano. Tale determinazione è giunta nel tempo ad avere una risoluzione molto spinta, dell’ordine di qualche chilometro, tuttavia una ionosonda tradizionale non possiede la capacità di individuare la struttura degli strati riflettenti

Evaluation of the IKKβ Binding of Indicaxanthin by Induced-Fit Docking, Binding Pose Metadynamics, and Molecular Dynamics

Background: Indicaxanthin, a betaxanthin belonging to the betalain class of compounds, has been recently demonstrated to exert significant antiproliferative effects inducing apoptosis of human melanoma cells through the inhibition of NF-κB as the predominant pathway. Specifically, Indicaxanthin inhibited IκBα degradation in A375 cells. In resting cells, NF-κB is arrested in the cytoplasm by binding to its inhibitor protein IκBα. Upon stimulation, IκBα is phosphorylated by the IKK complex, and degraded by the proteasome, liberating free NF-κB into the nucleus to initiate target gene transcription. Inhibition of the IKK complex leads to the arrest of the NF-κB pathway. Methods: To acquire details at the molecular level of Indicaxanthin’s inhibitory activity against hIKKβ, molecular modeling and simulation techniques including induced-fit docking (IFD), binding pose metadynamics (BPMD), molecular dynamics simulations, and MM-GBSA (molecular mechanics-generalized Born surface area continuum solvation) have been performed. Results: The computational calculations performed on the active and inactive form, and the allosteric binding site of hIKKβ, revealed that Indicaxanthin inhibits prevalently the active form of the hIKKβ. MM-GBSA computations provide further evidence of Indicaxanthin’s stability inside the active binding pocket with a binding free energy of −22.2 ± 4.3 kcal/mol with respect to the inactive binding pocket with a binding free energy of −20.7 ± 4.7 kcal/mol. BPMD and MD simulation revealed that Indicaxanthin is likely not an allosteric inhibitor of hIKKβ. Conclusion: As a whole, these in silico pieces of evidence show that Indicaxanthin can inhibit the active form of the hIKKβ adding novel mechanistic insights on its recently discovered ability to impair NF-κB signaling in melanoma A375 cells. Moreover, our results suggest the phytochemical as a new lead compound for novel, more potent IKKβ inhibitors to be employed in the treatment of cancer and inflammation-related conditions

In Silico Design, Synthesis and Biological Evaluation of Anticancer Arylsulfonamide Endowed with Anti-Telomerase Activity

Telomerase, a reverse transcriptase enzyme involved in DNA synthesis, has a tangible role in tumor progression. Several studies have evidenced telomerase as a promising target for developing cancer therapeutics. The main reason is due to the overexpression of telomerase in cancer cells (85–90%) compared with normal cells where it is almost unexpressed. In this paper, we used a structure-based approach to design potential inhibitors of the telomerase active site. The MYSHAPE (Molecular dYnamics SHared PharmacophorE) approach and docking were used to screen an in-house library of 126 arylsulfonamide derivatives. Promising compounds were synthesized using classical and green methods. Compound 2C revealed an interesting IC50 (33 ± 4 µM) against the K-562 cell line compared with the known telomerase inhibitor BIBR1532 IC50 (208 ± 11 µM) with an SI ~10 compared to the BALB/3-T3 cell line. A 100 ns MD simulation of 2C in the telomerase active site evidenced Phe494 as the key residue as well as in BIBR1532. Each moiety of compound 2C was involved in key interactions with some residues of the active site: Arg557, Ile550, and Gly553. Compound 2C, as an arylsulfonamide derivative, is an interesting hit compound that deserves further investigation in terms of optimization of its structure to obtain more active telomerase inhibitors

Rilevamento delle sorgenti doppler della ionosfera tramite radar-HF

Il presente lavoro contiene un insieme di concetti di base utili per comprendere la cosiddetta tecnica della “interferometria doppler”, usata, nell’ambito degli studi sulla ionosfera, per ricavare informazioni sulla conformazione e velocità degli strati riflettenti (operazione chiamata anche sky mapping). È utile ricordare, infatti, che il sondaggio ionosferico tradizionale consente solo la determinazione dell’altezza virtuale di ogni strato, pensato come un unico oggetto riflettente piano. Tale determinazione è giunta nel tempo ad avere una risoluzione molto spinta, dell’ordine di qualche chilometro, tuttavia una ionosonda tradizionale non possiede la capacità di individuare la struttura degli strati riflettenti

The new AIS-INGV digital ionosonde

A new digital ionosonde called AIS-INGV (Advanced Ionospheric Sounder) was designed both for research and for routine service of HF radio wave propagation forecast. Nearly the entire system was developed in the Laboratorio di Geofisica Ambientale at the Istituto Nazionale di Geofisica e Vulcanologia (INGV), Rome. It exploits advanced techniques for signal analysis, recent technological devices and PC resources. This paper describes design concepts and performance of the new ionosonde

THE NEW INGV DIGITAL IONOSONDE: DESIGN REPORT

The ionosonde is a system which exploits the radar technique: it applies electromagnetic waves with variable frequency in the HF band to measure the ionospheric layers electron density, height and other parameters. This paper is a technical report on the new digital ionosonde (AIS-INGV), which was designed both for research purposes and for the routine service of the HF radiowave propagation forecast. It has been developed almost completely within the Laboratorio di Geofisica Ambientale (LGA) at the Istituto Nazionale di Geofisica e Vulcanologia (INGV). It exploits advanced techniques for the signal analysis, recent technological devices and PC resources. The report is divided into two parts; the first is a general description of the design development, the second is a more detailed description of the blocks and circuits actually built and tested, directed to a specialist reader

Phytol and Heptacosane Are Possible Tools to Overcome Multidrug Resistance in an In Vitro Model of Acute Myeloid Leukemia

Drug resistance is the ability of cancer cells to gain resistance to both conventional and novel chemotherapy agents, and remains a major problem in cancer therapy. Resistance mechanisms are multifactorial and involve more strictly pharmacological factors, such as P-glycoprotein (P-gp) and biological factors such as inhibitor of apoptosis proteins (IAPs) and the nuclear factor-kappa B (NF-kB) pathway. Possible therapeutic strategies for the treatment of acute myeloid leukemia (AML) have increased in recent years; however, drug resistance remains a problem for most pa-tients. Phytol and heptacosane are the major compounds of Euphorbia intisy essential oil (EO) which were demonstrated to inhibit P-gp in a multidrug resistant in vitro model of AML. This study investigated the mechanism by which phytol and heptacosane improve P-gp-mediated drug transport. Phytol suppresses the P-gp expression via NF-kB inhibition and does not seem to act on the efflux system. Heptacosane acts as a substrate and potent P-gp inhibitor, demonstrating the ability to retain the substrate doxorubicin inside the cell and enhancing its cytotoxic effects. Our results suggest that these compounds act as non-toxic modulators of P-gp through different mechanisms and are able to revert P-gp-mediated drug resistance in tumor cells