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Structural Dynamics of Picornavirus replication complexes. Implications for the design of antivirals

AutorFerrer-Orta, Cristina ; Higuera, Ignacio de la ; Domingo, Esteban ; Verdaguer, Núria
Fecha de publicación26-oct-2012
CitaciónX SEQT Mini-Symposium (2012)
ResumenPicornaviruses are associated with important and diverse diseases, including poliomyelitis, hepatitis A, the common cold, febrile and respiratory illness in humans, and foot-and-mouth disease (FMD), the economically most important animal viral disease. These viruses have also been instrumental in establishing the relevance of high mutation rates for RNA viruses. RNA-dependent RNA polymerases (RdRPs) synthesize RNA using an RNA template and are normally associated with other virus- or/and host-encoded proteins that modulate RNA polymerization activity and template specificity. An important feature of RNA directed RNA replication is the high error frequency compared to DNA directed replication. This is due, at least in part, to the low fidelity of RdRPs and the absence of error-repair mechanisms in RNA viruses. A new strategy against RNA viruses consists in using mutagenic nucleotides. The objective is to provoke an excessive number of mutations, to deteriorate the viral functions to the point that the virus cannot survive. This strategy is called lethal mutagenesis (reviewed in Domingo et al. 2005). One of the mutagens used in research on lethal mutagenesis is the purine analogue termed ribavirin (1-(¿-D-ribofuranosyl)-1H-1,2,4-triazole-3-carboxamide), extensively employed in clinical practice. Unfortunately, viral mutants that are resistant to ribavirin have been selected, thus facilitating viral escape from lethal mutagenesis. The structural studies of different picornavirus replication complexes allowed to interpret the mutagenic activity of nucleoside analogues and helped to elucidate the molecular mechanisms of viral resistance. Among them, FMDV is the picornavirus with the most complete structural information on replication complexes available (reviewed in Ferrer-Orta et al., 2009). Five different crystal structures of foot-and-mouth disease virus (FMDV) 3D catalytic complexes have enhanced our understanding of template and primer recognition, rNTP binding and catalysis. Furthermore, the biochemical and structural analyses of eight different FMDV 3D ribavirin resistant mutants provided evidences of three different mechanisms of resistance to this mutagenic nucleoside analogue. Such structural information is providing new insights into the fidelity of RNA replication, and for the design of antiviral compounds.
DescripciónComunicación presentada en el X SEQT Mini-Symposium = X Jornadas de la SEQT (Soceidad Española de Química Terapéutica), "Highlights in Drug Discovery from Academia to Industry, celebrado el 25 y 26 de octubre de 2012 en Segovia (España)
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