Novel nucleosides as potent influenza viral inhibitors

Vedula, Manohar Sharma; Jennepalli, Sreenu; Aryasomayajula, Ratnakar; Rondla, Subhash Reddy; Musku, Madanmohan Reddy; Kura, Rathnakar Reddy; Bandi, Parthasaradhi Reddy

doi:10.1016/j.bmc.2010.07.017

Cited by 7 publications

(7 citation statements)

References 43 publications

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“…During more recent years, 2ʹ‐substituted carba‐nucleoside analogues , C‐3ʹ‐modified analogues , and 6‐methyl‐7‐substituted‐7‐deaza purine nucleoside analogues were reported to have anti‐influenza activity comparable to 2ʹ‐FdG. The antiviral activity of 2ʹ‐FdG and analogues is dependent on intracellular conversion to the active nucleoside 5ʹ‐triphosphate form.…”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

“…161 The identity of the amino acid changes in this mutant polymerase was not disclosed, which is unfortunate since this insight could be very helpful to explain the role of specific residues in the catalytic or other functional domain of PB1, as identified in the recent crystallographic studies. 23,24,56,58 During more recent years, 2ʹ-substituted carba-nucleoside analogues, 100 C-3ʹ-modified analogues, 102 and 6-methyl-7-substituted-7-deaza purine nucleoside analogues 103 were reported to have anti-influenza activity comparable to 2ʹ-FdG. The antiviral activity of 2ʹ-FdG and analogues is dependent on intracellular conversion to the active nucleoside 5ʹ-triphosphate form.…”

Section: ʹ-Deoxy-2ʹ-fluoroguanosine and Other Nucleoside Analoguesmentioning

confidence: 99%

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

Stevaert

Naesens

2016

Medicinal Research Reviews

138

151

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Influenza viruses cause seasonal epidemics and pandemic outbreaks associated with significant morbidity and mortality, and a huge cost. Since resistance to the existing anti‐influenza drugs is rising, innovative inhibitors with a different mode of action are urgently needed. The influenza polymerase complex is widely recognized as a key drug target, given its critical role in virus replication and high degree of conservation among influenza A (of human or zoonotic origin) and B viruses. We here review the major progress that has been made in recent years in unravelling the structure and functions of this protein complex, enabling structure‐aided drug design toward the core regions of the PA endonuclease, PB1 polymerase, or cap‐binding PB2 subunit. Alternatively, inhibitors may target a protein–protein interaction site, a cellular factor involved in viral RNA synthesis, the viral RNA itself, or the nucleoprotein component of the viral ribonucleoprotein. The latest advances made for these diverse pharmacological targets have yielded agents in advanced (i.e., favipiravir and VX‐787) or early clinical testing, besides several experimental inhibitors in various stages of development, which are all covered here.

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Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

confidence: 99%

Section: ʹ-Deoxy-2ʹ-fluoroguanosine and Other Nucleoside Analoguesmentioning

confidence: 99%

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

Stevaert

Naesens

2016

Medicinal Research Reviews

138

151

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“…Brivudine is an antiviral drug used in the treatment of herpes zoster (VZV) [2,4,7]. As to antiviral activity, the literature has provided just a few examples of nucleoside analogues which are influenza A virus inhibitors [8][9][10][11][12][13]. Among approved influenza drugs (Amantadine, Rimantadine, Zanamivir, Oseltamivir, Laninamivir octanoate, Peramivir, Favipiravir and Ribavirin [4]), there is only one nucleoside analogue, namely Ribavirin (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide) [4,7,[14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, the search for influenza drugs among nucleoside analogues has drawn very little attention of chemists and pharmacologists. This is despite the fact that influenza virus infection constitutes a significant health problem in need of more effective therapies [8]. The worldwide spread of drug-resistant influenza strains poses an urgent need for novel antiviral drugs, particularly with a different mechanism of action [10].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

et al. 2020

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Based on the fact that a search for influenza antivirals among nucleoside analogues has drawn very little attention of chemists, the present study reports the synthesis of a series of 1,2,3-triazolyl nucleoside analogues in which a pyrimidine fragment is attached to the ribofuranosyl-1,2,3-triazol-4-yl moiety by a polymethylene linker of variable length. Target compounds were prepared by the Cu alkyne-azide cycloaddition (CuAAC) reaction. Derivatives of uracil, 6-methyluracil, 3,6-dimethyluracil, thymine and quinazolin-2,4-dione with ω-alkyne substituent at the N1 (or N5) atom and azido 2,3,5-triO -acetyl-D-β-ribofuranoside were used as components of the CuAAC reaction. All compounds synthesized were evaluated for antiviral activity against influenza virus A/PR/8/34/(H1N1) and coxsackievirus B3. The best values of IC 50 (inhibiting concentration) and SI (selectivity index) were demonstrated by the lead compound 4i in which the 1,2,3-triazolylribofuranosyl fragment is attached to the N1 atom of the quinazoline-2,4-dione moiety via a butylene linker (IC 50 = 30 μM, SI = 24) and compound 8n in which the 1,2,3-triazolylribofuranosyl fragment is attached directly to the N5 atom of the 6-methyluracil moiety (IC 50 = 15 μM, SI = 5). According to theoretical calculations, the antiviral activity of the 1,2,3-triazolyl nucleoside analogues 4i and 8n against H1N1 (A/PR/8/34) influenza virus can be explained by their influence on the functioning of the polymerase acidic protein (PA) of RNA-dependent RNA polymerase (RdRP).

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“…2ʹ-Deoxy-2ʹ-fluoroguanosine (2'-FdG) (200) and other nucleoside analogues (such as C-3ʹ-modified analogues (201), 2ʹ-substituted carba-nucleoside analogues (202), 6-methyl-7-substituted-7-deaza purine nucleoside analogues (203) etc.) were reported to posess anti-influenza activities against influenza A and B viruses.…”

Section: Pb2 Cab-binding Inhibitorsmentioning

confidence: 99%

Progress of small molecular inhibitors in the development of anti-influenza virus agents

Wu¹,

Wu²,

Sun³

et al. 2017

Theranostics

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The influenza pandemic is a major threat to human health, and highly aggressive strains such as H1N1, H5N1 and H7N9 have emphasized the need for therapeutic strategies to combat these pathogens. Influenza anti-viral agents, especially active small molecular inhibitors play important roles in controlling pandemics while vaccines are developed. Currently, only a few drugs, which function as influenza neuraminidase (NA) inhibitors and M2 ion channel protein inhibitors, are approved in clinical. However, the acquired resistance against current anti-influenza drugs and the emerging mutations of influenza virus itself remain the major challenging unmet medical needs for influenza treatment. It is highly desirable to identify novel anti-influenza agents. This paper reviews the progress of small molecular inhibitors act as antiviral agents, which include hemagglutinin (HA) inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors, NA inhibitors and M2 ion channel protein inhibitors etc. Moreover, we also summarize new, recently reported potential targets and discuss strategies for the development of new anti-influenza virus drugs.

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Novel nucleosides as potent influenza viral inhibitors

Cited by 7 publications

References 43 publications

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

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

Synthesis of 1,2,3-triazolyl nucleoside analogues and their antiviral activity

Progress of small molecular inhibitors in the development of anti-influenza virus agents

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