RESUMEN
Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.
Asunto(s)
Antivirales/química , Virus del Dengue/enzimología , Inhibidores Enzimáticos/química , Metiltransferasas/antagonistas & inhibidores , Metiltransferasas/química , S-Adenosilmetionina/análogos & derivados , S-Adenosilmetionina/química , Proteínas Virales/antagonistas & inhibidores , Proteínas Virales/química , Antivirales/farmacología , Sitios de Unión , Cristalografía por Rayos X , Dengue/tratamiento farmacológico , Dengue/enzimología , Dengue/genética , Virus del Dengue/genética , Inhibidores Enzimáticos/farmacología , Humanos , Metiltransferasas/genética , Metiltransferasas/metabolismo , S-Adenosilmetionina/farmacología , Proteínas Virales/genética , Proteínas Virales/metabolismoRESUMEN
A novel class of compounds containing N-sulfonylanthranilic acid was found to specifically inhibit dengue viral polymerase. The structural requirements for inhibition and a preliminary structure-activity relationship are described. A UV cross-linking experiment was used to map the allosteric binding site of the compound on the viral polymerase.