RESUMO
The advent of the molecular biology and the completion of the human genome sequencing prompted the pharmaceutical industry to progressively implement target-centric drug discovery strategies. However, concerns regarding the research and development productivity during the last ten years, combined with technological developments in high-content screening, automation, image analysis and artificial intelligence triggered a renewed interest for the phenotypic drug discovery approaches. Target-centric and phenotypic approaches are more and more considered complementary, hence, positioning the target deconvolution on the critical path. This review analyzes the evolution of the target-centric and phenotypic approaches, focusing more specifically on the high-content screening and the target deconvolution technologies currently available.
TITLE: Du criblage à haut contenu à la déconvolution de cibles - Nouvelle donne pour les approches phénotypiques. ABSTRACT: L'avènement de la biologie moléculaire et l'achèvement du séquençage du génome humain ont conduit l'industrie pharmaceutique à progressivement implémenter des approches dites cible-centriques pour identifier les candidats médicaments. Cependant, la faible productivité de la recherche et du développement en ce début de millénaire, combinée aux évolutions technologiques dans des domaines tels que l'ingénierie cellulaire, le criblage à haut contenu, la robotique, l'analyse d'images et l'intelligence artificielle, ont nourri un fort regain d'intérêt pour les approches phénotypiques. De plus en plus fréquemment, les approches cible-centriques et phénotypiques sont considérées de façon complémentaire, positionnant ainsi les techniques de déconvolution1 de cible sur le chemin critique de la découverte et du développement de médicaments. Cette revue analyse l'évolution des approches cible-centriques versus phénotypiques, en se focalisant plus particulièrement sur le criblage à haut contenu et les différentes techniques de déconvolution de cible aujourd'hui disponibles.
Assuntos
Descoberta de Drogas/métodos , Humanos , Fenótipo , PesquisaRESUMO
Hibernation is an exceptional physiological response to a hostile environment, characterized by a seasonal period of torpor cycles involving dramatic reductions of body temperature and metabolism, and arousal back to normothermia. As the mechanisms regulating hibernation are still poorly understood, here we analysed the expression of genes involved in energy homeostasis, torpor regulation, and daily or seasonal timing using digital droplet PCR in various central and peripheral tissues sampled at different stages of torpor/arousal cycles in the European hamster. During torpor, the hypothalamus exhibited strongly down-regulated gene expression, suggesting that hypothalamic functions were reduced during this period of low metabolic activity. During both torpor and arousal, many structures (notably the brown adipose tissue) exhibited altered expression of deiodinases, potentially leading to reduced tissular triiodothyronine availability. During the arousal phase, all analysed tissues showed increased expression of the core clock genes Per1 and Per2. Overall, our data indicated that the hypothalamus and brown adipose tissue were the tissues most affected during the torpor/arousal cycle, and that clock genes may play critical roles in resetting the body's clocks at the beginning of the active period.