A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-α-2b and nucleoside analogues

Luscombe, Carolyn A.; Huang, Zhuhui; Murray, Michael G.; Miller, Michelle; Wilkinson, John; Ewart, Gary

doi:10.1016/j.antiviral.2010.02.312

Cited by 82 publications

(70 citation statements)

References 39 publications

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“…Similarly to hepaciviruses, p7 plays an essential role in the life cycle of pestiviruses and contributes to their pathogenicity (Gladue et al, 2012;Griffin et al, 2004;Luscombe et al, 2010). It has been argued that the pestivirus p7 constitutes a general model for the HCV p7 viroporin, therefore making it useful in the characterization of anti-HCV compounds (Griffin et al, 2004;Luscombe et al, 2010).…”

Section: Introductionmentioning

confidence: 98%

Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function

et al. 2014

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Section: Introductionmentioning

confidence: 98%

Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function

et al. 2014

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“…amantadine, rimantadine, and N-((5-(thiophen-2-yl)isoxazol-3-yl)methyl)-adamantan-1-amine (M2WJ352) (Wang et al, 2013b). (B) Acylguanidines: HMA (Gazina and Petrou, 2012), BIT-225 (Khoury et al, 2010;Luscombe et al, 2010), EIPA, and BIT-314.…”

Section: Methodsmentioning

confidence: 99%

“…HMA has also been reported to inhibit M2(WT) (IC 50 5 1.1 mM by TEVC) but not M2(S31N), whereas a related compound N-(5-(1-methyl-1H-pyrazol-4-yl)naphthalene-2-carbonyl)guanidine (BIT-225; Fig. 1B) inhibits currents from the viroporins of hepatitis C and HIV-1 and shows promising activity in early clinical trials (Khoury et al, 2010;Luscombe et al, 2010;Gazina and Petrou, 2012). Although additional acylguanidines, including ethyl-isopropyl amiloride (EIPA) and (6-(1-methylpryazol-4-yl)-2-napthoyl)guanidinium (BIT-314; Fig.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride

et al. 2016

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The increasing prevalence of influenza viruses with resistance to approved antivirals highlights the need for new anti-influenza therapeutics. Here we describe the functional properties of hexamethylene amiloride (HMA)-derived compounds that inhibit the wildtype and adamantane-resistant forms of the influenza A M2 ion channel. For example, 6-(azepan-1-yl)-N-carbamimidoylnicotinamide (9) inhibits amantadine-sensitive M2 currents with 3-to 6-fold greater potency than amantadine or HMA (IC 50 5 0.2 vs. 0.6 and 1.3 mM, respectively). Compound 9 competes with amantadine for M2 inhibition, and molecular docking simulations suggest that 9 binds at site(s) that overlap with amantadine binding. In addition, tert-butyl 49-(carbamimidoylcarbamoyl)-29,3-dinitro-

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“…Initial reports suggest that in related BVDV p7 functions as an ion channelforming protein (13). BVDV is sensitive to amantadine (13) and BIT225 (21), known inhibitors of HCV p7 ion channel function. Thus, it is hypothesized that CSFV p7, like HCV p7 and influenza virus M2 proteins, may function as a viroporin involved in pore formation and transport of ions across cell membranes (1,11).…”

mentioning

confidence: 99%

Classical Swine Fever Virus p7 Protein Is a Viroporin Involved in Virulence in Swine

Gladue

Holinka

Largo

et al. 2012

J Virol

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The nonstructural protein p7 of classical swine fever virus (CSFV) is a small hydrophobic polypeptide with an apparent molecular mass of 6 to 7 kDa. The protein contains two hydrophobic stretches of amino acids interrupted by a short charged segment that are predicted to form transmembrane helices and a cytosolic loop, respectively. Using reverse genetics, partial in-frame deletions of p7 were deleterious for virus growth, demonstrating that CSFV p7 function is critical for virus production in cell cultures. A panel of recombinant mutant CSFVs was created using alanine scanning mutagenesis of the p7 gene harboring sequential three- to six-amino-acid residue substitutions spanning the entire protein. These recombinant viruses allowed the identification of the regions within p7 that are critical for virus production in vitro. In vivo , some of these viruses were partially or completely attenuated in swine relative to the highly virulent parental CSFV Brescia strain, indicating a significant role of p7 in CSFV virulence. Structure-function analyses in model membranes emulating the endoplasmic reticulum lipid composition confirmed that CSFV p7 is a pore-forming protein, and that pore-forming activity resides in the C-terminal transmembrane helix. Therefore, p7 is a viroporin which is clearly involved in the process of CSFV virulence in swine.

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A novel Hepatitis C virus p7 ion channel inhibitor, BIT225, inhibits bovine viral diarrhea virus in vitro and shows synergism with recombinant interferon-α-2b and nucleoside analogues

Cited by 82 publications

References 39 publications

Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function

Pore-forming activity of pestivirus p7 in a minimal model system supports genus-specific viroporin function

Mechanisms of Action of Novel Influenza A/M2 Viroporin Inhibitors Derived from Hexamethylene Amiloride

Classical Swine Fever Virus p7 Protein Is a Viroporin Involved in Virulence in Swine

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