Obtenció de nous anàlegs amb activitat brassinoesteroide mitjançant modelització molecular i síntesi

Els brassinoesteroides són productes naturals que actuen com a potents reguladors del creixement vegetal. Presenten aplicacions prometedores en l’agricultura degut a que, aplicats exògenament, augmenten la qualitat i la quantitat de les collites. Ara bé, el seu ús s’ha vist restringit degut a la seva costosa obtenció. Aquest fet ha motivat la recerca de nous compostos actius més assequibles. En aquest projecte es planteja el disseny i obtenció de nous anàlegs seguint diferents estratègies que impliquen tant l’ús de mètodes de modelització molecular com de síntesi orgànica. La primera d’aquestes estratègies consisteix en buscar compostos actius en bases de dades de compostos comercials a través de processos de Virtual Screening desenvolupats amb mètodes computacionals basats en Camps d’Interacció Molecular. Així, es van establir i interpretar models de Relacions Quantitatives Estructura-Activitat (QSAR) emprant descriptors independents de l’alineament (GRIND) i, amb col•laboració amb la Universitat de Perugia, aquest criteri de cerca es va ampliar amb l’aplicació de descriptors FLAP de nova generació. Una altra estratègia es va basar en intentar substituir l’esquelet esteroide dels brassinoesteroides per una estructura equivalent, fixant com a cadena lateral el grup (R)-hexahidromandelil. S’han aplicat dos criteris: mètodes computacionals basats en models QSAR establerts amb descriptors GRIND i també en la metodologia SHOP (scaffold hopping), i, per altra banda, anàlegs proposats racionalment a partir d’un estudi efectuat sobre disruptors endocrins no esteroïdals. Sobre les estructures trobades s’hi va unir la cadena lateral comercial esmentada per via sintètica, en la qual s’ha hagut de fer un èmfasi especial en grups protectors. En total, 49 estructures es proposen per a ser obtingudes sintèticament. També s’ha treballat en l’obtenció un agonista derivat de l’hipotètic antagonista KM-01. Totes les molècules candidates, ja siguin comercials o obtingudes sintèticament, estant sent avaluades en el test d’inclinació de la làmina d’arròs (RLIT).

Antifungal compounds from plants

Due to the increase of the incidence of fungal infections in humans and the limitations of the available antimycotic drugs, among which the emergence of resistant strains, there is a need for the discovery of new antifungal agents. Plants, especially those used in Traditional Medicine, linked to an unmatched chemical diversity, either as pure compounds or as plant extracts, provide unlimited opportunities for the development of new antifungals. Inrecent years, compounds from different phytochemical groups have been described as having antifungal activity, including polyphenols, saponins, or peptides, among others, as well asessential oils and their constituents. After screening of ethnopharmacologically selected plants, mainly from Latin-America, followed by bio-guided isolation, our group hasdescribed the antifungal activity of different types of plant constituents, such as sesquiterpenes, triterpenes, flavonoids, lignans, fatty acids and essential oils.

The Protein quality control system manages plant defence compound synthesis

Jasmonates are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of many development, growth and defence processes. Across the plant kingdom, jasmonates act as elicitors of the production of bioactive secondarymetabolites that serve in defence against attackers. Knowledge of the conserved jasmonate perception and early signalling machineries is increasing, but the downstream mechanisms that regulate defence metabolism remain largely unknown. Herewe showthat, in the legumeMedicago truncatula, jasmonate recruits the endoplasmic-reticulum-associated degradation (ERAD)quality control system tomanagethe production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols. An ERAD-type RING membraneanchor E3 ubiquitin ligase is co-expressed with saponin synthesis enzymes to control the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thus, unrestrained bioactive saponin accumulationis prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that uses distinct E3 ubiquitin ligases, of the HMGR degradation 1 (HRD1) type, to direct destruction of HMGR. Hence, the general principles for the management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues.

The Protein quality control system manages plant defence compound synthesis

Jasmonates are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of many development, growth and defence processes. Across the plant kingdom, jasmonates act as elicitors of the production of bioactive secondarymetabolites that serve in defence against attackers. Knowledge of the conserved jasmonate perception and early signalling machineries is increasing, but the downstream mechanisms that regulate defence metabolism remain largely unknown. Herewe showthat, in the legumeMedicago truncatula, jasmonate recruits the endoplasmic-reticulum-associated degradation (ERAD)quality control system tomanagethe production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols. An ERAD-type RING membraneanchor E3 ubiquitin ligase is co-expressed with saponin synthesis enzymes to control the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thus, unrestrained bioactive saponin accumulationis prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that uses distinct E3 ubiquitin ligases, of the HMGR degradation 1 (HRD1) type, to direct destruction of HMGR. Hence, the general principles for the management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues.

The Protein quality control system manages plant defence compound synthesis

Jasmonates are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of many development, growth and defence processes. Across the plant kingdom, jasmonates act as elicitors of the production of bioactive secondarymetabolites that serve in defence against attackers. Knowledge of the conserved jasmonate perception and early signalling machineries is increasing, but the downstream mechanisms that regulate defence metabolism remain largely unknown. Herewe showthat, in the legumeMedicago truncatula, jasmonate recruits the endoplasmic-reticulum-associated degradation (ERAD)quality control system tomanagethe production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols. An ERAD-type RING membraneanchor E3 ubiquitin ligase is co-expressed with saponin synthesis enzymes to control the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thus, unrestrained bioactive saponin accumulationis prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that uses distinct E3 ubiquitin ligases, of the HMGR degradation 1 (HRD1) type, to direct destruction of HMGR. Hence, the general principles for the management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues.

The Protein quality control system manages plant defence compound synthesis

Jasmonates are ubiquitous oxylipin-derived phytohormones that are essential in the regulation of many development, growth and defence processes. Across the plant kingdom, jasmonates act as elicitors of the production of bioactive secondarymetabolites that serve in defence against attackers. Knowledge of the conserved jasmonate perception and early signalling machineries is increasing, but the downstream mechanisms that regulate defence metabolism remain largely unknown. Herewe showthat, in the legumeMedicago truncatula, jasmonate recruits the endoplasmic-reticulum-associated degradation (ERAD)quality control system tomanagethe production of triterpene saponins, widespread bioactive compounds that share a biogenic origin with sterols. An ERAD-type RING membraneanchor E3 ubiquitin ligase is co-expressed with saponin synthesis enzymes to control the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the rate-limiting enzyme in the supply of the ubiquitous terpene precursor isopentenyl diphosphate. Thus, unrestrained bioactive saponin accumulationis prevented and plant development and integrity secured. This control apparatus is equivalent to the ERAD system that regulates sterol synthesis in yeasts and mammals but that uses distinct E3 ubiquitin ligases, of the HMGR degradation 1 (HRD1) type, to direct destruction of HMGR. Hence, the general principles for the management of sterol and triterpene saponin biosynthesis are conserved across eukaryotes but can be controlled by divergent regulatory cues.