RESUMEN
We describe herein the design, syntheses and evaluation of a number of bicycloproline P2 bearing HCV protease inhibitors endowed with impressive enzyme potency, enzyme selectivity, cellular activity and favorable ADME profiles.
Asunto(s)
Hepacivirus/efectos de los fármacos , Prolina/química , Serina Endopeptidasas/metabolismo , Inhibidores de Serina Proteinasa/farmacología , Proteínas no Estructurales Virales/metabolismo , Animales , Compuestos Bicíclicos con Puentes/síntesis química , Compuestos Bicíclicos con Puentes/farmacología , Dipéptidos/síntesis química , Dipéptidos/farmacología , Hepacivirus/enzimología , Humanos , Masculino , Prolina/farmacología , Ratas , Ratas Sprague-Dawley , Inhibidores de Serina Proteinasa/síntesis químicaRESUMEN
Human herpesviruses are found worldwide and are among the most frequent causes of viral infections in immunocompetent as well as in immunocompromised patients. During the past decade and a half a better understanding of the replication and disease-causing state of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), and human cytomegalovirus (HCMV) has been achieved due in part to the development of potent antiviral compounds that target these viruses. While some of these antiviral therapies are considered safe and efficacious (acyclovir, penciclovir), some have toxicities associated with them (ganciclovir and foscarnet). In addition, the increased and prolonged use of these compounds in the clinical setting, especially for the treatment of immunocompromised patients, has led to the emergence of viral resistance against most of these drugs. While resistance is not a serious issue for immunocompetent individuals, it is a real concern for immunocompromised patients, especially those with AIDS and the ones that have undergone organ transplantation. All the currently approved treatments target the viral DNA polymerase. It is clear that new drugs that are more efficacious than the present ones, are not toxic, and target a different viral function would be of great use especially for immunocompromised patients. Here, an overview is provided of the diseases caused by the herpesviruses as well as the replication strategy of the better studied members of this family for which treatments are available. We also discuss the various drugs that have been approved for the treatment of some herpesviruses in terms of structure, mechanism of action, and development of resistance. Finally, we present a discussion of viral targets other than the DNA polymerase, for which new antiviral compounds are being considered.