Top-down and Bottom-up approach in the development of new bioactive chemical entities inspired on natural products scaffolds

Progetto: Research project

Dettagli progetto

Description

The project is aimed to the identification and development of new chemical entities inspired on natural products asinteractors of receptors involved in the metabolic syndrome.Metabolic syndrome is a clustering of several medical conditions, abdominal obesity, elevated blood pressure,hypercholesterolemia, hypertriglyceridemia, and diabetes. Metabolic syndrome associates with cardiovascular diseases and isbecoming more common, due to a rise in obesity among adults.Through a novel experimental platform that involves what might be called “Top-down and Bottom-up” approach, ourattention will be focused on bile acid receptors, FXR and GPBAR1, on AhR and on proteasome 26S, whose relevance in thedevelopment of metabolic syndrome has been strongly implicated in the literature. The project has a multidisciplinarystructure including all the steps of drug discovery: isolation, total synthesis, SAR studies, design, molecular investigation onligand/receptor interaction, pharmacological in vitro evaluation with the final aim to propose to the bio-pharmaceuticalcommunity new hits for the treatment of metabolic diseases.Top-down method is a target-oriented, chemical-guided approach. The study will be aimed to the discovery of new analoguesof “privileged” natural chemical scaffolds able to exert modulatory activity on the selected targets. In the first step, thechemical study of terrestrial and marine sources known as producers of isoprenoid and polyphenol secondary metaboliteswould allow the identification of natural potential leads. A multiparametric analysis of the interaction of the isolatedcompounds with their partners will be performed (NMR, computational chemistry, mass spectrometry, ALPHA screen,fluorescence, surface plasmon resonance, functional proteomics, in vitro pharmacological evaluation) and the results will behelpful for a medicinal chemistry approach in the design and synthesis of simplified analogs, a step that will be alsocomplemented by synthetic studies on molecules already known to interact with the selected targets.Bottom-up method is a target-oriented bioactivity-guided approach aimed to expand the chemodiversity of the availablemodulators through the discovery of new natural metabolites with novel structural features. The study will mainly focus onmarine organisms selected on the basis of preliminary pharmacological assays. In silico and functional proteomic methodswill be applied for the characterization of the interactome profile and in the identification of the best candidates. Thechemodiversity will be also expanded through the selection of molecules from LIBIOMOL, the first chemical library on naturaland natural-derived bioactive products, created in the frame of PRIN09.Since their usual scarce recovery from the natural sources, a bio-sustainable production of the selected natural hits will bealso investigated to provide adequate amounts for future investigations.

Layman's description

The project is aimed at the identification and development of new chemical entities inspired on natural product scaffolds as interactors of selected nuclear, membrane and cytosolic receptors involved in the metabolic syndrome.Obesity is a complex metabolic disease that is a major risk factor for the development of T2DM and cardiovascular diseases.More than one-third of adults and 17% of youth in the US are obese, with high-calorie/high-fat food being the major causefor these global health issues.We have chosen to converge to the expected goal of the project from two different points of view, planning a novel experimental platform, the “Top-down and Bottom-up approach”.Top-down method is a target-oriented, chemical-guided approach aimed to the discovery and development of new analogues of “privileged” natural chemical scaffolds able to exert modulatory activity on the selected targets, recently identified as key factors in the development of the metabolic syndrome.Bottom-up method is a target-oriented bioactivity-guided approach aimed to expand the chemodiversity of the availablemodulators through the discovery of new natural metabolites with novel structural features.Specifically, our attention will be focused on bile acid receptors, FXR and GPBAR1, on AhR and on proteasome 26S, whose relevance in the development of metabolic syndrome has been strongly implicated in the literature.In the liver, FXR works as a sensor of bile acids (BAs). Upon BA binding, FXR forms a heterodimer with the retinoid Xreceptor (RXR) that binds specific DNA sequences within the promoter regions of target genes. The canonical geneexpression program activated by FXR leads to the reduction in intracellular BA levels by increasing the export out of cells,decreasing uptake and synthesis.In addition, FXR plays a crucial beneficial role in hepatic triglyceride homeostasis, as well as in glucose metabolism. Indeed,BAs can also signal through the membrane GPBAR1. Responses to GPBAR1 activation include increased energy expenditure,improved glucose metabolism and insulin sensitivity. Therefore, the exogenous regulation of these two receptors representsan attractive strategy to treat severe enterohepatic and metabolic disorders such as NASH, hypercholesterolemia,hypertriglyceridemia, and T2DM.AhR is a cytosolic transcription factor involved in several pathophysiological events leading to immunosuppression andcancer. Whereas this receptor still requires de-orphanization, with no endogenous ligands so far identified, several planarhalogenated polycyclic hydrocarbons, such as dioxins and biphenyl or polycyclic aromatic hydrocarbons displayed highagonistic affinity to AhR, which resulted in epigenetic carcinogen and tumor promoter activities of these persistentcontaminants. In addition, recent epidemiological studies indicate that AhR activation by dioxins associates with an increasedrisk of obesity and T2DM. Indeed, the study of the effects of AhR agonists, or antagonists or weak agonists, revealedconflicting outcomes with clear discrepancies in reported activities of AhR signaling. Therefore, the discovery of newmodulators of this receptor could offer new insights in deciphering the role of complex AhR-mediated signaling in severalhuman pathologies, from cancer to metabolic syndrome.The proteasome, a complex multimeric structure located both in the cytoplasm and in the nucleus, is responsible for thedegradation of short-lived, damaged and misfolded newly synthesized proteins. Since its functional involvement in relevantpathways ruling the cell life, proteasome has gained

Key findings

Salute
StatoFinito
Data di inizio/fine effettiva2/5/172/4/20