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

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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“…B) that appears to interact with the influenza vRNA promoter. This molecule was found to inhibit virus replication in a plaque reduction assay …”

Section: Strategies To Interfere With the Influenza Virus Polymerasementioning

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

136

151

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“…The first viral RNA regulatory elements shown to be bound and interfered with by small molecules were the HIV transactivation response (TAR) (Mei, et al, 1995) and Rev response element (RRE) (Zapp, et al, 1993). Other viral RNAs such as the hepatitis C virus internal ribosomal entry site (HCV IRES) and Influenza A have been focus of several targeting studies (Dibrov, et al, 2014; Lee, et al, 2014). Recently, several small molecules have been designed to target nucleotide repeat expansions including fragile X-associated tremor ataxia syndrome (FXTAS; CGG) (Yang, et al, 2016), myotonic dystrophy type 1 (DM1; CUG) (Gareiss, et al, 2008; Jahromi, et al, 2013; Pushechnikov, et al, 2009), myotonic dystrophy type 2 (DM2; CCUG) (Childs-Disney, et al, 2014), Huntington’s disease (HD; CAG) (Kumar, et al, 2012), and frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALD; G 4 C 2 ) (Su, et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs

Velagapudi

Costales

Vummidi

et al. 2018

Cell Chemical Biology

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Potential RNA drug targets for small molecules are found throughout the human transcriptome, yet small molecules known to elicit a pharmacological response by directly targeting RNA are limited to antibacterials. Herein, we describe AbsorbArray, a small molecule microarray-based approach that allows for unmodified compounds, including FDA-approved drugs, to be probed for binding to RNA motif libraries in a massively parallel format. Several drug classes bind RNA including kinase and topoisomerase inhibitors. The latter avidly bound the motif found in the Dicer site of oncogenic microRNA (miR)-21 and inhibited its processing both in vitro and in cells. The most potent compound de-repressed a downstream protein target and inhibited a miR-21-mediated invasive phenotype. The compound's activity was ablated upon overexpression of pre-miR-21. Target validation via chemical crosslinking and isolation by pull-down showed direct engagement of pre-miR-21 by the small molecule in cells, demonstrating that RNAs should indeed be considered druggable.

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“…NMR spectroscopy was further successfully applied for the identification of fragment-like molecules binding to the influenza A virus RNA promoter [121]. Different influenza A virus subtypes carry viral RNAs in their genome with highly conserved nucleotides on their 5 0 -as well as their 3 0 -ends.…”

Section: Ligands Discovered By Fragment Screening On Rna Targetsmentioning

confidence: 99%

Structure-Based Discovery of Small Molecules Binding to RNA

Wehler

Brenk

2017

Topics in Medicinal Chemistry

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Ribonucleic acids (RNAs) constitute attractive drug targets. The wealth of structural information about RNAs is steadily increasing making it possible to use this information for the design of new ligands. Two methods that make heavy use of structural knowledge for ligand discovery are molecular docking and fragment screening. In molecular docking the structure of the binding site is used as a template for the design of new ligands using computational methods whereas in fragment screening biophysical methods are used for the detection of weak binding ligands which are subsequently elaborated into tighter binding molecules. In this chapter, we give an overview of both methods in the context of ligand discovery for RNA targets and illustrate their applications for hit discovery.

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

Cited by 56 publications

References 16 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

Approved Anti-cancer Drugs Target Oncogenic Non-coding RNAs

Structure-Based Discovery of Small Molecules Binding to RNA

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