Structural Investigation of Cycloheptathiophene-3-carboxamide Derivatives Targeting Influenza Virus Polymerase Assembly

Massari, Serena; Nannetti, Giulio; Goracci, Laura; Sancineto, Luca; Muratore, Giulia; Sabatini, Stefano; Manfroni, Giuseppe; Mercorelli, Beatrice; Cecchetti, Violetta; Facchini, Marzia; Palù, Giorgio; Cruciani, Gabriele; Loregian, Arianna; Tabarrini, Oriana

doi:10.1021/jm401560v

Cited by 51 publications

(109 citation statements)

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“…While our transmissible H7N1 virus does not harbor mutations that confer resistance to existing antivirals, amantadine resistance is prevalent in circulating human influenza viruses and oseltamivir-resistant viruses are being isolated with increasing frequency (50)(51)(52). The mutations in NP and PB2 highlight the need for strategies that specifically target the viral polymerase, and several compounds are currently under development (53)(54)(55)(56)(57)(58). For example, nucleozin causes NP oligomerization in the cytoplasm, limiting nuclear import and assembly of vRNPs (55), and cycloheptathiophene-3-carboxamide derivatives inhibit PB1-PA interactions (56).…”

Section: Discussionmentioning

confidence: 99%

“…The mutations in NP and PB2 highlight the need for strategies that specifically target the viral polymerase, and several compounds are currently under development (53)(54)(55)(56)(57)(58). For example, nucleozin causes NP oligomerization in the cytoplasm, limiting nuclear import and assembly of vRNPs (55), and cycloheptathiophene-3-carboxamide derivatives inhibit PB1-PA interactions (56). Importantly, as mutations in the internal genes appear to be a determinant in the evolution of the transmission phenotype, the use of antiviral agents targeting the viral polymerase during outbreaks could slow or prevent the emergence of a virus capable of airborne transmission and/or causing a pandemic.…”

Section: Discussionmentioning

confidence: 99%

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Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets

Sutton

Finch

Shao

et al. 2014

J Virol

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Avian H7 influenza viruses are recognized as potential pandemic viruses, as personnel often become infected during poultry outbreaks. H7 infections in humans typically cause mild conjunctivitis; however, the H7N9 outbreak in the spring of 2013 has resulted in severe respiratory disease. To date, no H7 viruses have acquired the ability for sustained transmission among humans. Airborne transmission is considered a requirement for the emergence of pandemic influenza, and advanced knowledge of the molecular changes or signature required for transmission would allow early identification of pandemic vaccine seed stocks, screening and stockpiling of antiviral compounds, and eradication efforts focused on flocks harboring threatening viruses. Thus, we sought to determine if a highly pathogenic influenza A H7N1 (A/H7N1) virus with no history of human infection could become capable of airborne transmission among ferrets. We show that after 10 serial passages, A/H7N1 developed the ability to be transmitted to cohoused and airborne contact ferrets. Four amino acid mutations (PB2 T81I, NP V284M, and M1 R95K and Q211K) in the internal genes and a minimal amino acid mutation (K/R313R) in the stalk region of the hemagglutinin protein were associated with airborne transmission. Furthermore, transmission was not associated with loss of virulence. These findings highlight the importance of the internal genes in host adaptation and suggest that natural isolates carrying these mutations be further evaluated. Our results demonstrate that a highly pathogenic avian H7 virus can become capable of airborne transmission in a mammalian host, and they support ongoing surveillance and pandemic H7 vaccine development. IMPORTANCEThe major findings of this report are that a highly pathogenic strain of H7N1 avian influenza virus can be adapted to become capable of airborne transmission in mammals without mutations altering receptor specificity. Changes in receptor specificity have been shown to play a role in the ability of avian influenza viruses to cross the species barrier, and these changes are assumed to be essential. The work reported here challenges this paradigm, at least for the influenza viruses of the H7 subtype, which have recently become the focus of major attention, as they have crossed to humans.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets

Sutton

Finch

Shao

et al. 2014

J Virol

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“…[29,30] In particular, Knoevenagel condensation of the cycloheptanone with 2-cyano-N-pyridin-2-ylacetamide [31] or 2-cyano-N-(2-fluorophenyl)acetamide, [31] followed by cyclization performed in the presence of sulfur and N,N-diethylamine in ethanol gave compounds 38 [27] and 39, respectively. Compounds 23-25, 28-31, and 34-36 were then obtained by coupling reactions of intermediate 38 with the appropriate acyl chlorides in dry pyridine.…”

Section: Synthesis Of Chtc Derivativesmentioning

confidence: 99%

“…[20] Considering our continuous interest in the anti-HIV field, [7,9,15,[21][22][23][24][25][26] we noted a strict structural similarity between the vinylogous ureas [16][17][18] of a series of cycloheptathiophene-3-carboxamide (cHTC) derivatives (Figure 1) recently reported by us as influenza virus inhibitors based on their ability to disrupt interaction of the polymerase acidic protein (PA)-polymerase basic protein 1 (PB1) subunits of the viral RNA polymerase. [27,28] Thus, we decided to assay a set of these compounds for antiRNase H activity. The promising results led to the synthesis of other analogues with the aim to improve the anti-RNase H activity and perform an in-depth investigation on their mechanism of action.…”

Section: Introductionmentioning

confidence: 99%

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

et al. 2016

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Despite the significant progress achieved with combination antiretroviral therapy in the fight against human immunodeficiency virus (HIV) infection, the difficulty to eradicate the virus together with the rapid emergence of multidrug-resistant strains clearly underline a pressing need for innovative agents, possibly endowed with novel mechanisms of action. In this context, owing to its essential role in HIV genome replication, the reverse transcriptase associated ribonuclease H (RNase H) has proven to be an appealing target. To identify new RNase H inhibitors, an in-house cycloheptathiophene-3-carboxamide library was screened; this led to compounds endowed with inhibitory activity, the structural optimization of which led to the catechol derivative 2-(3,4-dihydroxybenzamido)-N-(pyridin-2-yl)-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carboxamide (compound 33) with an IC50 value on the RNase H activity in the nanomolar range. Mechanistic studies suggested selective inhibition of the RNase H through binding to an innovative allosteric site, which could be further exploited to enrich this class of inhibitors.

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“…Reported biologic activities for tetrahydrobenzothiophenes include inhibition of tyrosine kinase receptor FLT3 (Patch et al, 2006) and influenza virus RNA polymerase assembly (Massari et al, 2013). Both thioxoaminothiazoles and tetrahydrobenzothiophenes can be prepared in three to five steps from commercially available starting materials, thus allowing facile and rapid diversification of these scaffolds for further medicinal chemistry and structure-activity relationship efforts to improve biologic activities and pharmacological properties.…”

Section: δF508-cftr Potentiatorsmentioning

confidence: 99%

Potentiators of Defective ΔF508–CFTR Gating that Do Not Interfere with Corrector Action

et al. 2015

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Combination drug therapies under development for cystic fibrosis caused by the ΔF508 mutation in cystic fibrosis transmembrane conductance regulator (CFTR) include a "corrector" to improve its cellular processing and a "potentiator" to improve its chloride channel function. Recently, it was reported that the approved potentiator N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Ivacaftor) reduces ΔF508-CFTR cellular stability and the efficacy of investigational correctors, including 3-, which might contribute to the modest reported efficacy of combination therapy in clinical trials. Here, we report the identification and characterization of potentiators that do not interfere with ΔF508-CFTR stability or corrector action. Highthroughput screening and structure-activity analysis identified several classes of potentiators that do not impair corrector action, including tetrahydrobenzothiophenes, thiooxoaminothiazoles, and pyrazole-pyrrole-isoxazoles. The most potent compounds have an EC 50 for ΔF508-CFTR potentiation down to 18 nM and do not reduce corrector efficacy in heterologous ΔF508-CFTRexpressing cells or primary cultures of ΔF508/ΔF508 human bronchial epithelia. The DF508-CFTR potentiators also activated wild-type and G551D CFTR, albeit weakly. The efficacy of combination therapy for cystic fibrosis caused by the ΔF508 mutation may be improved by replacement of Ivacaftor with a potentiator that does not interfere with corrector action.

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Structural Investigation of Cycloheptathiophene-3-carboxamide Derivatives Targeting Influenza Virus Polymerase Assembly

Cited by 51 publications

References 50 publications

Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets

Airborne Transmission of Highly Pathogenic H7N1 Influenza Virus in Ferrets

Studies on Cycloheptathiophene‐3‐carboxamide Derivatives as Allosteric HIV‐1 Ribonuclease H Inhibitors

Potentiators of Defective ΔF508–CFTR Gating that Do Not Interfere with Corrector Action

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