Superstolide A : a potent cytotoxic macrolide of a new type from the New Caledonian deep water marine sponge Neosiphonia superstes

A highly cytotoxic macrolide, superstolide A (1), has been isolated from the deep water marine sponge Neosiphonia superstes, collected off New Caledonia. The gross structure was determined by extensive 2D NMR experiments on the lactone 1 and on its opened-ring-derived methyl esters 2 and 3. The relative stereochemistries of the decaline moiety and of the C22-C26 fragment were determined by a combination of NMR data and acetonide analysis on 2. Absolute stereostructure of the decaline portion of 1 has been determined on the basis of GLC-modified Horeau's methodology applied to 4, whereas the results of the application of the modified Mosher's method to 1 and 3 allowed us to propose for the C22-C26 fragment the 22R, 23R, 24R, 25S, 26R configuration. We also propose the solution conformations of superstolide A (1) based on molecular dynamics and mechanics calculations using NMR-derived constraints

Computational approaches to shed light on molecular mechanisms in biological processes

Computational approaches based on Molecular Dynamics simulations, Quantum Mechanical methods and 3D Quantitative Structure-Activity Relationships were employed by computational chemistry groups at the University of Milano-Bicocca to study biological processes at the molecular level. The paper reports the methodologies adopted and the results obtained on Aryl hydrocarbon Receptor and homologous PAS proteins mechanisms, the properties of prion protein peptides, the reaction pathway of hydrogenase and peroxidase enzymes and the defibrillogenic activity of tetracyclines. © Springer-Verlag 2007

Three new potent cytotoxic macrolides closely related to sphinxolide from the New Caledonia sponge Neosiphonia superstes

Three new macrolides 2-4 have been isolated with sphinxolide 1 from the marine sponge #N. superstes$ collected off New Caledonia. The structures of the new compounds were determined by interpretation of NMR spectral data as well as comparison of spectral data with those of 1. These compounds were highly cytotoxic against various human carcinoma cells. (Résumé d'auteur

Improved heuristic drift elimination with magnetically-aided dominant directions (MiHDE) for pedestrian navigation in complex buildings

The main problem of pedestrian dead-reckoning (PDR) using only a body-attached inertial measurement unit is the accumulation of heading errors. The heading provided by magnetometers in indoor buildings is in general not reliable and therefore it is commonly not used. Recently, a new method was proposed called heuristic drift elimination (HDE) that minimises the heading error when navigating in buildings. It assumes that the majority of buildings have their corridors parallel to each other, or they intersect at right angles, and consequently most of the time the person walks along a straight path with a heading constrained to one of the four possible directions. In this article we study the performance of HDE-based methods in complex buildings, i.e. with pathways also oriented at 45°, long curved corridors, and wide areas where non-oriented motion is possible. We explain how the performance of the original HDE method can be deteriorated in complex buildings, and also, how severe errors can appear in the case of false matches with the building's dominant directions. Although magnetic compassing indoors has a chaotic behaviour, in this article we analyse large data-sets in order to study the potential use that magnetic compassing has to estimate the absolute yaw angle of a walking person. Apart from these analysis, this article also proposes an improved HDE method called Magnetically-aided Improved Heuristic Drift Elimination (MiHDE), that is implemented over a PDR framework that uses foot-mounted inertial navigation with an extended Kalman filter (EKF). The EKF is fed with the MiHDE-estimated orientation error, gyro bias corrections, as well as the confidence over that corrections. We experimentally evaluated the performance of the proposed MiHDE-based PDR method, comparing it with the original HDE implementation. Results show that both methods perform very well in ideal orthogonal narrow-corridor buildings, and MiHDE outperforms HDE for non-ideal trajectories (e.g. curved paths) and also makes it robust against potential false dominant direction matchings

Metabolites of the new Caledonian sponge Cladocroce incurvata

The deep-water New Caledonian sponge #Cladocroce incurvata$ contains two "polyketide" metabolites. Cladocrocin A (1) appears to be derived from fatty acid with ethyl side chains, thus incorporating butyrate units. Cladocroic acid (2) is a straight chain fatty acid which incorporates a terminal enyne functionality and a cycloproprane ring directly attached to the carboxylic acid function. The structures were elucidated by interpretation of spectral data, and the cis stereochemistry of the cyclopropane ring in cladocroic acid (2) was derived after the synthesis of cis - and trans - 2, 3 - methanohexanoic acid models and nmr spectral comparisons. (Résumé d'auteur

GLP-1 Mediates Regulation of Colonic ACE2 Expression by the Bile Acid Receptor GPBAR1 in Inflammation

Background & Aims: ACE2, a carboxypeptidase that generates Ang-(1-7) from Ang II, is highly expressed in the lung, small intestine and colon. GPBAR1, is a G protein bile acid receptor that promotes the release of the insulinotropic factor glucagon-like peptide (GLP)-1 and attenuates intestinal inflammation. Methods: We investigated the expression of ACE2, GLP-1 and GPBAR1 in two cohorts of Crohn’s disease (CD) patients and three mouse models of colitis and Gpbar1−/− mice. Activation of GPBAR1 in these models and in vitro was achieved by BAR501, a selective GPBAR1 agonist. Results: In IBD patients, ACE2 mRNA expression was regulated in a site-specific manner in response to inflammation. While expression of ileal ACE2 mRNA was reduced, the colon expression was induced. Colon expression of ACE2 mRNA in IBD correlated with expression of TNF-α and GPBAR1. A positive correlation occurred between GCG and GPBAR1 in human samples and animal models of colitis. In these models, ACE2 mRNA expression was further upregulated by GPABR1 agonism and reversed by exendin-3, a GLP-1 receptor antagonist. In in vitro studies, liraglutide, a GLP-1 analogue, increased the expression of ACE2 in colon epithelial cells/macrophages co-cultures. Conclusions: ACE2 mRNA expression in the colon of IBD patients and rodent models of colitis is regulated in a TNF-α-and GLP-1-dependent manner. We have identified a GPBAR1/GLP-1 mechanism as a positive modulator of ACE2

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In light of the urgent need to identify novel approaches to be used in the emergency phase, we have embarked on an exploratory campaign aimed at repurposing natural substances and clinically available drugs as potential anti-SARS-CoV2-2 agents by targeting viral proteins. Here we report on a strategy based on the virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike's protein receptor binding domain (RBD). By combining an in silico approach and molecular in vitro testing we have been able to identify several triterpenoid/steroidal agents that inhibit interaction of the Spike RBD with the carboxypeptidase domain of the Angiotensin Converting Enzyme (ACE2). In detail, we provide evidence that potential binding sites exist in the RBD of the SARS CoV-2 Spike protein and that occupancy of these pockets reduces the ability of the RBD to bind to the ACE2 consensus in vitro. Naturally occurring and clinically available triterpenoids such as glycyrrhetinic and oleanolic acids, as well as primary and secondary bile acids and their amidated derivatives such as glyco-ursodeoxycholic acid and semi-synthetic derivatives such as obeticholic acid reduces the RBD/ACE2 binding. In aggregate, these results might help to define novel approaches to COVID-19 based on SARS-CoV-2 entry inhibitors