scholarly journals The Influenza Virus Polymerase Complex: An Update on Its Structure, Functions, and Significance for Antiviral Drug Design

2016 ◽  
Vol 36 (6) ◽  
pp. 1127-1173 ◽  
Author(s):  
Annelies Stevaert ◽  
Lieve Naesens
Keyword(s):  
Influenza Virus ◽  
Drug Design ◽  
Antiviral Drug ◽  
Structure Functions ◽  
Polymerase Complex

scholarly journals The amyloidogenicity of the influenza virus PB1-derived peptide sheds light on its antiviral activity

2017 ◽  
Author(s):  
Yana A. Zabrodskaya ◽  
Dmitry V. Lebedev ◽  
Marja A. Egorova ◽  
Aram A. Shaldzhyan ◽  
Alexey V. Shvetsov ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Antiviral Activity ◽  
Antiviral Drug ◽  
Alpha Helix ◽  
Terminal Region ◽  
Helical Conformation ◽  
Amino Acid Residues ◽  
Polymerase Complex ◽  
Low Concentrations ◽  
Promising Target

AbstractThe influenza virus polymerase complex is a promising target for new antiviral drug development. It is known that, within the influenza virus polymerase complex, the PB1 subunit region from the 1st to the 25th amino acid residues has to be is in an alpha-helical conformation for proper interaction with the PA subunit. We have previously shown that PB1(6–13) peptide at low concentrations is able to interact with the PB1 subunit N-terminal region in a peptide model which shows aggregate formation and antiviral activity in cell cultures.In this paper, it was shown that PB1(6–13) peptide is prone to form the amyloid-like fibrillar aggregates. The peptide homo-oligomerization kinetics were examined, and the affinity and characteristic interaction time of PB1(6–13) peptide monomers and the influenza virus polymerase complex PB1 subunit N-terminal region were evaluated by the SPR and TR-SAXS methods. Based on the data obtained, a hypothesis about the PB1(6–13) peptide mechanism of action was proposed: the peptide in its monomeric form is capable of altering the conformation of the PB1 subunit N-terminal region, causing a change from an alpha helix to a beta structure. This conformational change disrupts PB1 and PA subunit interaction and, by that mechanism, the peptide displays antiviral activity.Graphical abstract

Flexibility as a Strategy in Nucleoside Antiviral Drug Design

2015 ◽  
Vol 22 (34) ◽  
pp. 3910-3921 ◽  
Author(s):  
H. Peters ◽  
T. Ku ◽  
K. Seley-Radtke
Keyword(s):  
Drug Design ◽  
Antiviral Drug

scholarly journals Network-Guided Discovery of Influenza Virus Replication Host Factors

mBio ◽  
2018 ◽  
Vol 9 (6) ◽  
Author(s):  
Emily E. Ackerman ◽  
Eiryo Kawakami ◽  
Manami Katoh ◽  
Tokiko Watanabe ◽  
Shinji Watanabe ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Replication ◽  
Virus Replication ◽  
Drug Targets ◽  
Antiviral Drug ◽  
Viral Proteins ◽  
Host Factors ◽  
Ppi Network ◽  
Host Proteins ◽  
Influenza Virus Replication

ABSTRACTThe positions of host factors required for viral replication within a human protein-protein interaction (PPI) network can be exploited to identify drug targets that are robust to drug-mediated selective pressure. Host factors can physically interact with viral proteins, be a component of virus-regulated pathways (where proteins do not interact with viral proteins), or be required for viral replication but unregulated by viruses. Here, we demonstrate a method of combining human PPI networks with virus-host PPI data to improve antiviral drug discovery for influenza viruses by identifying target host proteins. Analysis shows that influenza virus proteins physically interact with host proteins in network positions significant for information flow, even after the removal of known abundance-degree bias within PPI data. We have isolated a subnetwork of the human PPI network that connects virus-interacting host proteins to host factors that are important for influenza virus replication without physically interacting with viral proteins. The subnetwork is enriched for signaling and immune processes distinct from those associated with virus-interacting proteins. Selecting proteins based on subnetwork topology, we performed an siRNA screen to determine whether the subnetwork was enriched for virus replication host factors and whether network position within the subnetwork offers an advantage in prioritization of drug targets to control influenza virus replication. We found that the subnetwork is highly enriched for target host proteins—more so than the set of host factors that physically interact with viral proteins. Our findings demonstrate that network positions are a powerful predictor to guide antiviral drug candidate prioritization.IMPORTANCEIntegrating virus-host interactions with host protein-protein interactions, we have created a method using these established network practices to identify host factors (i.e., proteins) that are likely candidates for antiviral drug targeting. We demonstrate that interaction cascades between host proteins that directly interact with viral proteins and host factors that are important to influenza virus replication are enriched for signaling and immune processes. Additionally, we show that host proteins that interact with viral proteins are in network locations of power. Finally, we demonstrate a new network methodology to predict novel host factors and validate predictions with an siRNA screen. Our results show that integrating virus-host proteins interactions is useful in the identification of antiviral drug target candidates.

scholarly journals Effect of the preparation Ingavirin® (imidazolyl ethanamide pentandioic acid) on the interferon status of cells under conditions of viral infection

2016 ◽  
Vol 21 (4) ◽  
pp. 196-205
Author(s):  
Thomas Aschacher ◽  
Artem Krokhin ◽  
Irina Kuznetsova ◽  
Johannes Langle ◽  
Vladimir Nebolsin ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Viral Infection ◽  
Viral Infections ◽  
Antiviral Drug ◽  
Effector Proteins ◽  
Theoretical Ground ◽  
Ns1 Protein ◽  
Interferon Inducer ◽  
Infected Cells ◽  
Interferon System

Ingavirin® (imidazolyl ethanamide pentandioic acid) is an original antiviral drug, which is used in Russia for treatment and profilaxis of influenza and other acute viral infections. We confirmed that imidazolyl ethanamide pentandioic acid (IEPA), not being interferon inducer itself, enhances synthesis of both interferon-a/fi receptors (IFNAR) to interferone and cell sensitivity to interferone signalling, which was suppressed by NS1 protein - pathogen factor of influenza virus. IEPA is able to promote antiviral effector proteins PKR and MxA in infected cells, in opposition to interferon system suppression by influenza virus. Theoretical ground of clinical efficacy of Ingavirine® could be confirmed by obtained data of influence to innate immune system during viral infection.

scholarly journals Involvement of Hsp90 in Assembly and Nuclear Import of Influenza Virus RNA Polymerase Subunits

2006 ◽  
Vol 81 (3) ◽  
pp. 1339-1349 ◽  
Author(s):  
Tadasuke Naito ◽  
Fumitaka Momose ◽  
Atsushi Kawaguchi ◽  
Kyosuke Nagata
Keyword(s):  
Influenza Virus ◽  
Rna Polymerase ◽  
Nuclear Transport ◽  
Intracellular Localization ◽  
Viral Rna ◽  
Polymerase Complex ◽  
Virus Rna ◽  
Binary Complexes ◽  
Infected Cells ◽  
Rna Polymerase Subunits

ABSTRACT Transcription and replication of the influenza virus RNA genome occur in the nuclei of infected cells through the viral RNA-dependent RNA polymerase consisting of PB1, PB2, and PA. We previously identified a host factor designated RAF-1 (RNA polymerase activating factor 1) that stimulates viral RNA synthesis. RAF-1 is found to be identical to Hsp90. Here, we examined the intracellular localization of Hsp90 and viral RNA polymerase subunits and their molecular interaction. Hsp90 was found to interact with PB2 and PB1, and it was relocalized to the nucleus upon viral infection. We found that the nuclear transport of Hsp90 occurs in cells expressing PB2 alone. The nuclear transport of Hsp90 was in parallel with that of the viral RNA polymerase binary complexes, either PB1 and PB2 or PB1 and PA, as well as with that of PB2 alone. Hsp90 also interacted with the binary RNA polymerase complex PB1-PB2, and it was dissociated from the PB1-PB2 complex upon its association with PA. Furthermore, Hsp90 could form a stable PB1-PB2-Hsp90 complex prior to the formation of a ternary polymerase complex by the assembly of PA in the infected cells. These results suggest that Hsp90 is involved in the assembly and nuclear transport of viral RNA polymerase subunits, possibly as a molecular chaperone for the polymerase subunits prior to the formation of a mature ternary polymerase complex.

scholarly journals Detailed Molecular Interactions of Favipiravir with SARS-CoV-2, SARS-CoV, MERS-CoV, and Influenza Virus Polymerases In Silico

2020 ◽  
Vol 8 (10) ◽  
pp. 1610 ◽  
Author(s):  
Mitsuru Sada ◽  
Takeshi Saraya ◽  
Haruyuki Ishii ◽  
Kaori Okayama ◽  
Yuriko Hayashi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Molecular Interactions ◽  
In Silico ◽  
Influenza A ◽  
Active Sites ◽  
Active Form ◽  
Antiviral Drug ◽  
Virus Rna ◽  
Influenza A H1n1 ◽  
In Silico Studies

Favipiravir was initially developed as an antiviral drug against influenza and is currently used in clinical trials against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection (COVID-19). This agent is presumably involved in RNA chain termination during influenza virus replication, although the molecular interactions underlying its potential impact on the coronaviruses including SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV) remain unclear. We performed in silico studies to elucidate detailed molecular interactions between favipiravir and the SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza virus RNA-dependent RNA polymerases (RdRp). As a result, no interactions between favipiravir ribofuranosyl-5′-triphosphate (F-RTP), the active form of favipiravir, and the active sites of RdRps (PB1 proteins) from influenza A (H1N1)pdm09 virus were found, yet the agent bound to the tunnel of the replication genome of PB1 protein leading to the inhibition of replicated RNA passage. In contrast, F-RTP bound to the active sites of coronavirus RdRp in the presence of the agent and RdRp. Further, the agent bound to the replicated RNA terminus in the presence of agent, magnesium ions, nucleotide triphosphate, and RdRp proteins. These results suggest that favipiravir exhibits distinct mechanisms of action against influenza virus and various coronaviruses.

Antiviral drug design: computational analyses of the effects of the L100I mutation for HIV-RT on the binding of NNRTIs

2001 ◽  
Vol 11 (21) ◽  
pp. 2799-2802 ◽  
Author(s):  
De-Ping Wang ◽  
Robert C Rizzo ◽  
Julian Tirado-Rives ◽  
William L Jorgensen
Keyword(s):  
Drug Design ◽  
Antiviral Drug ◽  
Hiv Rt ◽  
Computational Analyses
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