scholarly journals A novel small-molecule compound disrupts influenza A virus PB2 cap-binding and inhibits viral replication

2016 ◽  
Vol 71 (9) ◽  
pp. 2489-2497 ◽  
Author(s):  
Shuofeng Yuan ◽  
Hin Chu ◽  
Ke Zhang ◽  
Jiahui Ye ◽  
Kailash Singh ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Small Molecule ◽  
Influenza A ◽  
Small Molecule Compound

scholarly journals A novel small-molecule binds to the influenza A virus RNA promoter and inhibits viral replication

2014 ◽  
Vol 50 (3) ◽  
pp. 368-370 ◽  
Author(s):  
Mi-Kyung Lee ◽  
Angel Bottini ◽  
Meehyein Kim ◽  
Michael F. Bardaro ◽  
Ziming Zhang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Small Molecule ◽  
Influenza A ◽  
Virus Rna ◽  
Rna Promoter

A Small-Molecule Compound Has Anti-influenza A Virus Activity by Acting as a ‘‘PB2 Inhibitor”

2018 ◽  
Vol 15 (9) ◽  
pp. 4110-4120 ◽  
Author(s):  
Teng Liu ◽  
Miaomiao Liu ◽  
Feimin Chen ◽  
Fangzhao Chen ◽  
Yuanxin Tian ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Small Molecule ◽  
Influenza A ◽  
Virus Activity ◽  
Small Molecule Compound

scholarly journals Identification of a novel small-molecule compound targeting the influenza A virus polymerase PB1-PB2 interface

2017 ◽  
Vol 137 ◽  
pp. 58-66 ◽  
Author(s):  
Shuofeng Yuan ◽  
Hin Chu ◽  
Jiahui Ye ◽  
Kailash Singh ◽  
Ziwei Ye ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Small Molecule ◽  
Influenza A ◽  
Small Molecule Compound

scholarly journals Correction: A novel small-molecule binds to the influenza A virus RNA promoter and inhibits viral replication

2014 ◽  
Vol 50 (83) ◽  
pp. 12578-12578 ◽  
Author(s):  
Mi-Kyung Lee ◽  
Angel Bottini ◽  
Meehyein Kim ◽  
Michael F. Bardaro ◽  
Ziming Zhang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Small Molecule ◽  
Influenza A ◽  
Virus Rna ◽  
Rna Promoter

scholarly journals Cyclophilin A interacts with influenza A virus M1 protein and impairs the early stage of the viral replication

2009 ◽  
Vol 11 (5) ◽  
pp. 730-741 ◽  
Author(s):  
Xiaoling Liu ◽  
Lei Sun ◽  
Maorong Yu ◽  
Zengfu Wang ◽  
Chongfeng Xu ◽  
...  
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Early Stage ◽  
Cyclophilin A ◽  
M1 Protein

scholarly journals Functional Analysis of PA Binding by Influenza A Virus PB1: Effects on Polymerase Activity and Viral Infectivity

2001 ◽  
Vol 75 (17) ◽  
pp. 8127-8136 ◽  
Author(s):  
Daniel R. Perez ◽  
Ruben O. Donis
Keyword(s):  
Amino Acids ◽  
Influenza Virus ◽  
Amino Acid ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Amino Acid Sequences ◽  
Influenza Viruses ◽  
Virus Growth ◽  
Transcription And Replication

ABSTRACT Influenza A virus expresses three viral polymerase (P) subunits—PB1, PB2, and PA—all of which are essential for RNA and viral replication. The functions of P proteins in transcription and replication have been partially elucidated, yet some of these functions seem to be dependent on the formation of a heterotrimer for optimal viral RNA transcription and replication. Although it is conceivable that heterotrimer subunit interactions may allow a more efficient catalysis, direct evidence of their essentiality for viral replication is lacking. Biochemical studies addressing the molecular anatomy of the P complexes have revealed direct interactions between PB1 and PB2 as well as between PB1 and PA. Previous studies have shown that the N-terminal 48 amino acids of PB1, termed domain α, contain the residues required for binding PA. We report here the refined mapping of the amino acid sequences within this small region of PB1 that are indispensable for binding PA by deletion mutagenesis of PB1 in a two-hybrid assay. Subsequently, we used site-directed mutagenesis to identify the critical amino acid residues of PB1 for interaction with PA in vivo. The first 12 amino acids of PB1 were found to constitute the core of the interaction interface, thus narrowing the previous boundaries of domain α. The role of the minimal PB1 domain α in influenza virus gene expression and genome replication was subsequently analyzed by evaluating the activity of a set of PB1 mutants in a model reporter minigenome system. A strong correlation was observed between a functional PA binding site on PB1 and P activity. Influenza viruses bearing mutant PB1 genes were recovered using a plasmid-based influenza virus reverse genetics system. Interestingly, mutations that rendered PB1 unable to bind PA were either nonviable or severely growth impaired. These data are consistent with an essential role for the N terminus of PB1 in binding PA, P activity, and virus growth.

scholarly journals Organization of the Influenza A Virus Genomic RNA in the Viral Replication Cycle—Structure, Interactions, and Implications for the Emergence of New Strains

Pathogens ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 951
Author(s):  
Julita Piasecka ◽  
Aleksandra Jarmolowicz ◽  
Elzbieta Kierzek
Keyword(s):  
Viral Replication ◽  
Influenza A Virus ◽  
Rna Structure ◽  
Influenza A ◽  
Respiratory Infections ◽  
Specific Interaction ◽  
Replication Cycle ◽  
Genome Packaging ◽  
Functional Roles ◽  
Interaction Sites

The influenza A virus is a human pathogen causing respiratory infections. The ability of this virus to trigger seasonal epidemics and sporadic pandemics is a result of its high genetic variability, leading to the ineffectiveness of vaccinations and current therapies. The source of this variability is the accumulation of mutations in viral genes and reassortment enabled by its segmented genome. The latter process can induce major changes and the production of new strains with pandemic potential. However, not all genetic combinations are tolerated and lead to the assembly of complete infectious virions. Reports have shown that viral RNA segments co-segregate in particular circumstances. This tendency is a consequence of the complex and selective genome packaging process, which takes place in the final stages of the viral replication cycle. It has been shown that genome packaging is governed by RNA–RNA interactions. Intersegment contacts create a network, characterized by the presence of common and strain-specific interaction sites. Recent studies have revealed certain RNA regions, and conserved secondary structure motifs within them, which may play functional roles in virion assembly. Growing knowledge on RNA structure and interactions facilitates our understanding of the appearance of new genome variants, and may allow for the prediction of potential reassortment outcomes and the emergence of new strains in the future.

scholarly journals Deep Mutational Scan of the Highly Conserved Influenza A Virus M1 Matrix Protein Reveals Substantial Intrinsic Mutational Tolerance

2019 ◽  
Vol 93 (13) ◽  
Author(s):  
Nancy Hom ◽  
Lauren Gentles ◽  
Jesse D. Bloom ◽  
Kelly K. Lee
Keyword(s):  
Cell Culture ◽  
Influenza Virus ◽  
Amino Acid ◽  
Viral Replication ◽  
Influenza A Virus ◽  
Influenza A ◽  
Matrix Protein ◽  
Influenza Virus Infection ◽  
Sequence Diversity ◽  
Virus Protein

ABSTRACTInfluenza A virus matrix protein M1 is involved in multiple stages of the viral infectious cycle. Despite its functional importance, our present understanding of this essential viral protein is limited. The roles of a small subset of specific amino acids have been reported, but a more comprehensive understanding of the relationship between M1 sequence, structure, and virus fitness remains elusive. In this study, we used deep mutational scanning to measure the effect of every amino acid substitution in M1 on viral replication in cell culture. The map of amino acid mutational tolerance we have generated allows us to identify sites that are functionally constrained in cell culture as well as sites that are less constrained. Several sites that exhibit low tolerance to mutation have been found to be critical for M1 function and production of viable virions. Surprisingly, significant portions of the M1 sequence, especially in the C-terminal domain, whose structure is undetermined, were found to be highly tolerant of amino acid variation, despite having extremely low levels of sequence diversity among natural influenza virus strains. This unexpected discrepancy indicates that not all sites in M1 that exhibit high sequence conservation in nature are under strong constraint during selection for viral replication in cell culture.IMPORTANCEThe M1 matrix protein is critical for many stages of the influenza virus infection cycle. Currently, we have an incomplete understanding of this highly conserved protein’s function and structure. Key regions of M1, particularly in the C terminus of the protein, remain poorly characterized. In this study, we used deep mutational scanning to determine the extent of M1’s tolerance to mutation. Surprisingly, nearly two-thirds of the M1 sequence exhibits a high tolerance for substitutions, contrary to the extremely low sequence diversity observed across naturally occurring M1 isolates. Sites with low mutational tolerance were also identified, suggesting that they likely play critical functional roles and are under selective pressure. These results reveal the intrinsic mutational tolerance throughout M1 and shape future inquiries probing the functions of this essential influenza A virus protein.

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