RESUMO
Normal anterior pituitary function is essential for fertility. Release from the gland of the reproductive hormones luteinising hormone and follicle-stimulating hormone is regulated primarily by hypothalamically-derived gonadotrophin-releasing hormone (GnRH), although other releasing factors (RF) have been postulated to exist. Using a bioinformatic approach, we have identified a novel peptide, phoenixin, that regulates pituitary gonadotrophin secretion by modulating the expression of the GnRH receptor, an action with physiologically relevant consequences. Compromise of phoenixin in vivo using small interfering RNA resulted in the delayed appearance of oestrus and a reduction in GnRH receptor expression in the pituitary. Phoenixin may represent a new class of hypothalamically-derived pituitary priming factors that sensitise the pituitary to the action of other RFs, rather than directly stimulating the fusion of secretary vesicles to pituitary membranes.
Assuntos
Hormônios Hipotalâmicos/metabolismo , Hormônios Peptídicos/metabolismo , Hormônios Hipofisários/isolamento & purificação , Reprodução/genética , Sequência de Aminoácidos , Animais , Células Cultivadas , Clonagem Molecular , Relação Dose-Resposta a Droga , Feminino , Fármacos para a Fertilidade/química , Fármacos para a Fertilidade/isolamento & purificação , Fármacos para a Fertilidade/metabolismo , Fármacos para a Fertilidade/farmacologia , Hormônio Liberador de Gonadotropina/genética , Hormônio Liberador de Gonadotropina/metabolismo , Hormônios Hipotalâmicos/genética , Hormônios Hipotalâmicos/isolamento & purificação , Hormônios Hipotalâmicos/farmacologia , Hormônio Luteinizante/sangue , Masculino , Dados de Sequência Molecular , Hormônios Peptídicos/genética , Hormônios Peptídicos/isolamento & purificação , Hormônios Peptídicos/farmacologia , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Hormônios Hipofisários/farmacologia , Ratos , Ratos Sprague-Dawley , Reprodução/efeitos dos fármacos , Reprodução/fisiologia , Homologia de Sequência de AminoácidosRESUMO
This review focuses on our approach to the study of the effect of a series of phosphoramidate substituted nucleoside analogs on model systems for cancer, HIV and fertility. This approach allowed the development of compound WHI-07, an arylphosphoramidate derivative of zidavudine. This compound is a multifunctional agent showing potent activity in the above mentioned model systems. Our rational drug design provided such a powerful derivative with all the necessary characteristic of a drug candidate. Importantly, we have experimental evidence that each of the groups associated with the molecular frame of WHI-07 imparts the multifunctional ability for this agent. In addition, we have also suggested a possible biological pathway for WHI-07 including various products with their therapeutic targets that are formed during the course of its metabolism inside the cell. We also propose which individual moieties in the structure of WHI-07 are responsible for the biological activity from the formation of these metabolites. A detailed structure-activity relationship is presented in the review in connection with various structural modifications of the agent. Application of this active agent in animal models shows the potential usefulness of this agent as a drug candidate. We further plan to utilize gene-chip technology to identify new targets and modes of action using microarrays to measure expression changes in thousands of gene products. In conclusion, we have demonstrated the power of multifunctional drug design to discover drugs to combat various diseases. We believe this is the future direction of the drug discovery process.