RESUMO
Mononegavirales, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV). Unfortunately, no effective vaccines and antiviral therapeutics against many Mononegavirales are currently available. Viral polymerases have been attractive and major antiviral therapeutic targets. Therefore, Mononegavirales polymerases have been extensively investigated for their structures and functions. Mononegavirales mimic RNA synthesis of their eukaryotic counterparts by utilizing multifunctional RNA polymerases to replicate entire viral genomes and transcribe viral mRNAs from individual viral genes as well as synthesize 5' methylated cap and 3' poly(A) tail of the transcribed viral mRNAs. The catalytic subunit large protein (L) and cofactor phosphoprotein (P) constitute the Mononegavirales polymerases. In this review, we discuss the shared and unique features of RNA synthesis, the monomeric multifunctional enzyme L, and the oligomeric multimodular adapter P of Mononegavirales We outline the structural analyses of the Mononegavirales polymerases since the first structure of the vesicular stomatitis virus (VSV) L protein determined in 2015 and highlight multiple high-resolution cryo-electron microscopy (cryo-EM) structures of the polymerases of Mononegavirales, namely, VSV, RABV, HRSV, human metapneumovirus (HMPV), and human parainfluenza virus (HPIV), that have been reported in recent months (2019 to 2020). We compare the structures of those polymerases grouped by virus family, illustrate the similarities and differences among those polymerases, and reveal the potential RNA synthesis mechanisms and models of highly conserved Mononegavirales We conclude by the discussion of remaining questions, evolutionary perspectives, and future directions.
Assuntos
Mononegavirais/enzimologia , Mononegavirais/genética , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , Proteínas Virais/química , Proteínas Virais/genética , Animais , Microscopia Crioeletrônica , Humanos , Metapneumovirus , Modelos Moleculares , Mononegavirais/classificação , Conformação Proteica , RNA Mensageiro , RNA Viral/genética , Vírus da Raiva , Vírus Sincicial Respiratório Humano , Vírus da Estomatite Vesicular Indiana/enzimologia , Vírus da Estomatite Vesicular Indiana/genética , Replicação ViralRESUMO
The Mononegavirales virus group comprises several major human pathogens, including measles, rabies and Ebola viruses. This article reports a computational analysis of the C-terminal region of RNA-dependent RNA-polymerases from Mononegavirales. Using a combination of sequence similarity and threading analysis, a 2'-O-ribose methyltransferase domain was identified that is involved in the capping of viral mRNAs.
Assuntos
RNA Polimerases Dirigidas por DNA/química , RNA Polimerases Dirigidas por DNA/genética , Metiltransferases/química , Metiltransferases/genética , Mononegavirais/enzimologia , Capuzes de RNA/metabolismo , Processamento Pós-Transcricional do RNA , Sequência de Aminoácidos , RNA Polimerases Dirigidas por DNA/metabolismo , Humanos , Metiltransferases/metabolismo , Dados de Sequência Molecular , Mononegavirais/genética , Estrutura Terciária de Proteína , RNA Viral/metabolismo , Alinhamento de SequênciaRESUMO
Worldwide, respiratory syncytial virus (RSV) causes severe disease in infants, the elderly, and immunocompromised people. No vaccine or effective antiviral treatment is available. RSV is a member of the non-segmented, negative-strand (NNS) group of RNA viruses and relies on its RNA-dependent RNA polymerase to transcribe and replicate its genome. Because of its essential nature and unique properties, the RSV polymerase has proven to be a good target for antiviral drugs, with one compound, ALS-8176, having already achieved clinical proof-of-concept efficacy in a human challenge study. In this article, we first provide an overview of the role of the RSV polymerase in viral mRNA transcription and genome replication. We then review past and current approaches to inhibiting the RSV polymerase, including use of nucleoside analogs and non-nucleoside inhibitors. Finally, we consider polymerase inhibitors that hold promise for treating infections with other NNS RNA viruses, including measles and Ebola.
Assuntos
Antivirais/uso terapêutico , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Mononegavirais/efeitos dos fármacos , Vírus Sincicial Respiratório Humano/efeitos dos fármacos , Antivirais/farmacologia , Ensaios Clínicos como Assunto , RNA Polimerases Dirigidas por DNA/efeitos dos fármacos , RNA Polimerases Dirigidas por DNA/metabolismo , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Doença pelo Vírus Ebola/tratamento farmacológico , Humanos , Sarampo/tratamento farmacológico , Mononegavirais/enzimologia , Mononegavirais/genética , Nucleosídeos/agonistas , RNA Mensageiro , RNA Polimerase Dependente de RNA/efeitos dos fármacos , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Vírus Sincicial Respiratório Humano/enzimologia , Vírus Sincicial Respiratório Humano/genética , Transcrição Gênica , Replicação Viral/efeitos dos fármacosRESUMO
Phosphorylation of one or more viral proteins is probably an essential step in the life cycle of every member of the nonsegmented negative-strand RNA virus (mononegavirales [MNV]) group. Since no virally encoded protein kinases have been discovered in this group, phosphorylation is effected entirely by host cell kinases. The virally encoded P proteins of the MNV are the only ones consistently phosphorylated with a stoichiometry > or =1. The P protein of vesicular stomatitis virus (VSV), and perhaps also of respiratory syncytial virus, are the only ones for which a function of phosphorylation has been established. Phosphorylation by casein kinase 2 at one or more identified sites in the VSV P protein activates transcriptional activity by promoting formation of a homotrimer, which is then capable of binding the RNA polymerase and attaching it to the N protein-RNA template. A second phosphorylation of VSV P protein by a different kinase also occurs, dependent upon prior modification by casein kinase 2, but its function is not definitely known. Phosphorylation of the other MNV P proteins may serve a different purpose. No evidence has been obtained yet for any function for phosphorylation of any other MNV protein.