A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase

Paeshuyse, Jan; Letellier, Carine; Froeyen, Matheus; Dutartre, Hélène; Vrancken, Robert; Canard, Bruno; Clercq, Erik De; Gueiffier, Alain; Teulade, Jean‐Claude; Herdewijn, Piet; Puerstinger, Gerhard; Koenen, F.; Kerkhofs, Pierre; Baraldi, Pier Giovanni; Neyts, Johan

doi:10.1016/j.antiviral.2009.02.192

Cited by 26 publications

(29 citation statements)

References 41 publications

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“…The effect of inhibitory compounds was evaluated on both the West Nile polymerase virus (WN-NS5) and the bovine viral diarrhea polymerase virus (BVDV-NS5) according to polymerase assays previously described [5,8]. Various concentrations (0, 0.5, 1, 5, 10, 20, 50, and 100 µM) of the compound were tested in each polymerase assay and the IC 50 s were determined in the same way as for the DV-NS5 RdRp.…”

Section: Effect Of Inhibitory Compounds On Different Virus Polymerasesmentioning

confidence: 99%

Biflavonoids ofDacrydium balansaewith Potent Inhibitory Activity on Dengue 2 NS5 Polymerase

et al. 2012

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In order to find new molecules for antiviral drug design, we screened 102 ethyl acetate extracts from New-Caledonian flora for antiviral activity against the dengue 2 virus RNA-dependant RNA polymerase (DV-NS5 RdRp). The leaf extract of Dacrydium balansae, which strongly inhibited the DV-NS5, was submitted to bioguided fractionation. Four biflavonoids ( 1- 4), three sterols ( 5- 7), and two stilbene derivatives ( 8- 9) were identified and evaluated for their antiviral potential on the DV-NS5 RdRp. Biflavonoids appeared to be potent inhibitors of DV-NS5 RdRp with IC (50)s between 0.26 and 3.12 µM. Inhibitory activity evaluations against the RNA polymerase from other Flaviviridae viruses allowed us to conclude that these compounds are specific inhibitors of the DV RNA polymerase. The strongest inhibitions were observed with hinokiflavone ( 4), but podocarpusflavone A ( 2) is the strongest noncytotoxic inhibitor of the DV-NS5 and it also displayed polymerase inhibitory activity in a DV replicon. A preliminary structure-activity relationship study (SARs) revealed the necessity of the biflavonoid skeleton, the influence of number and position of methoxylations, and the importance of a free rotation of the linkage between the two apigenin monomers of the biflavonoids. To the best of our knowledge, podocarpusflavone A ( 2) is the strongest noncytotoxic non-nucleotide molecule exhibiting a specific inhibitory activity against the RNA polymerase domain of DV-NS5 and thus is promising for chemotherapy development against dengue fever.

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Section: Effect Of Inhibitory Compounds On Different Virus Polymerasesmentioning

confidence: 99%

Biflavonoids ofDacrydium balansaewith Potent Inhibitory Activity on Dengue 2 NS5 Polymerase

et al. 2012

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“…In the BVDV RdRp crystal structure, both N264 and A392 are located in the vicinity of F224, a residue that was mutated in BVDV resistant mutants selected with other nonnucleoside inhibitors (NNIs), such as BPIP (29) (28). Molecular modeling revealed that F224 is located near the fingertip domain of the RdRp and that F224, I390, A392, and L225 are amino acids that limit the cavity where these compounds bind.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone

Castro¹,

Fabián

Caputto

et al. 2011

J Virol

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In the present work, we described the activity of the thiosemicarbazone derived from 5,6-dimethoxy-1-indanone (TSC), which we previously characterized as a new compound that inhibits bovine viral diarrhea virus (BVDV) infection. We showed that TSC acts at a point of time that coincides with the onset of viral RNA synthesis and that it inhibits the activity of BVDV replication complexes (RCs). Moreover, we have selected five BVDV mutants that turned out to be highly resistant to TSC but still susceptible to ribavirin (RBV). Four of these resistant mutants carried an N264D mutation in the viral RNA-dependent RNA polymerase (RdRp). The remaining mutant showed an A392E mutation within the same protein. Some of these mutants replicated slower than the wild-type (wt) virus in the absence of TSC, whereas others showed a partial reversion to the wt phenotype over several passages in the absence of the compound. The docking of TSC in the crystal structure of the BVDV RdRp revealed a close contact between the indane ring of the compound and several residues within the fingers domain of the enzyme, some hydrophobic contacts, and hydrogen bonds with the thiosemicarbazone group. Finally, in the mutated RdRp from resistant BVDV, these interactions with TSC could not be achieved. Interestingly, TSC inhibited BVDV replication in cell culture synergistically with RBV. In conclusion, TSC emerges as a new nonnucleoside inhibitor of BVDV RdRp that is synergistic with RBV, a feature that turns it into a potential compound to be evaluated against hepatitis C virus (HCV).

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“…34 [In collaboration with Pier Giovanni Baraldi we recently identified a pyrazolotriazolopyrimidinamine (LZ37, an A 2A adenosine receptor antagonist), as a selective BVDV inhibitor targeted at the viral RdRp. 35 ] Apparently, all these compounds, BPIP, VP32947, and AG110, interact at the same finger domain of RdRp, close to the amino acid residues F224 and E291, as they all lead to cross-resistance to one another (for BPIP this interaction is shown in Fig. 2B).…”

Section: D1 Cada Compounds As Down-modulators Of the Cellular Hiv Rementioning

confidence: 98%

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

Clercq

2009

Medicinal Research Reviews

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This review article presents the fourth part (part D) in the series of stories on antiviral drug discovery. The stories told in part D focus on: (i) the cyclotriazadisulfonamide compounds; (ii) the {5-[(4-bromophenylmethyl]-2-phenyl-5H-imidazo[4,5-c]pyridine} compounds; (iii) (1H,3H-thiazolo[3,4-a]benzimidazole) derivatives; (iv) T-705 (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) and (v) its structurally closely related analogue pyrazine 2-carboxamide (pyrazinamide); (vi) new strategies for the treatment of hemorrhagic fever virus infections, including, as the most imminent, (vii) dengue fever, (viii) the veterinary use of acyclic nucleoside phosphonates; (ix) the potential (off-label) use of cidofovir in the treatment of papillomatosis, particularly RRP (recurrent respiratory papillomatosis); and (x) finally, the prophylactic use of tenofovir to prevent HIV infections.

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A pyrazolotriazolopyrimidinamine inhibitor of bovine viral diarrhea virus replication that targets the viral RNA-dependent RNA polymerase

Cited by 26 publications

References 41 publications

Biflavonoids ofDacrydium balansaewith Potent Inhibitory Activity on Dengue 2 NS5 Polymerase

Biflavonoids ofDacrydium balansaewith Potent Inhibitory Activity on Dengue 2 NS5 Polymerase

Inhibition of Bovine Viral Diarrhea Virus RNA Synthesis by Thiosemicarbazone Derived from 5,6-Dimethoxy-1-Indanone

Yet another ten stories on antiviral drug discovery (part D): Paradigms, paradoxes, and paraductions

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