Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase

Rouvière, Claire Pierra; Amador, Agnès; Badaroux, Eric; Convard, Thierry; Costa, Daniel Da; Dukhan, David; Griffe, Ludovic; Griffon, Jean-François; LaColla, M.; Leroy, Frédéric; Liuzzi, Michel; Loi, A. G.; McCarville, Joe; Mascia, Valeria; Milhau, Julien; Onidi, Loredana; Paparin, Jean-Laurent; Rahali, Rachid; Sais, Efisio; Seifer, Maria; Surleraux, Dominique; Standring, David N.; Dousson, Cyril B.

doi:10.1016/j.bmcl.2016.01.042

Cited by 12 publications

(6 citation statements)

References 21 publications

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“…Several drugs such as filibuvir and lomibuvir bind to the thumb domain, whereas dasabuvir, GSK5852, HCV-796 bind to the palm domain. , Phosphonamidate bioisosterism has been reported to represent a new class of non-nucleoside inhibitors of HCV NS5B. The sulfonamide and amide groups were modified in the small molecules, 231 and 232 (Figure ), respectively, which are non-nucleoside NS5B inhibitors that bind to the allosteric site 2 of the thumb domain of the HCV viral polymerase (Figure ) …”

Section: Phosphonamidate Bioisosteresmentioning

confidence: 93%

“…G.McCarvilleJ.MasciaV.MilhauJ.OnidiL.PaparinJ. L.RahaliR.SaisE.SeiferM.SurlerauxD.StandringD.DoussonC. Pierra Rouviere, C. Amador, A. Badaroux, E. Convard, T. Da Costa, D. Dukhan, D. Griffe, L. Griffon, J. F. LaColla, M. Leroy, F. Liuzzi, M. Loi, A. G. McCarville, J. Mascia, V. Milhau, J. Onidi, L. Paparin, J. L. Rahali, R. Sais, E. Seifer, M. Surleraux, D. Standring, D. Dousson, C. Bioorganic & Medicinal Chemistry Letters . Copyright 2016 Elsevier.…”

Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

“…Compound 232 had potent activity in genotypes 1a and 1b infections in preclinical trials. In order to test the hypothesis of phosphonamidate bioisosterism, two compounds, 233 and 234 , were synthesized and evaluated for inhibition of HCV replication in the HCV replicon luciferase assay and inhibition of the 1b-J4 HCV NS5B polymerase . Only compound 234 produced a modest inhibition of the NS5B polymerase (IC 50 = 3.74 μM).…”

Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

See 2 more Smart Citations

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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The amide functional group plays a key role in the composition of biomolecules, including many clinically approved drugs. Bioisosterism is widely employed in the rational modification of lead compounds, being used to increase potency, enhance selectivity, improve pharmacokinetic properties, eliminate toxicity, and acquire novel chemical space to secure intellectual property. The introduction of a bioisostere leads to structural changes in molecular size, shape, electronic distribution, polarity, pK a, dipole or polarizability, which can be either favorable or detrimental to biological activity. This approach has opened up new avenues in drug design and development resulting in more efficient drug candidates introduced onto the market as well as in the clinical pipeline. Herein, we review the strategic decisions in selecting an amide bioisostere (the why), synthetic routes to each (the how), and success stories of each bioisostere (the implementation) to provide a comprehensive overview of this important toolbox for medicinal chemists.

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Section: Phosphonamidate Bioisosteresmentioning

confidence: 93%

Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

Section: Phosphonamidate Bioisosteresmentioning

confidence: 99%

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Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

et al. 2020

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“…Phosphonamidates are not only used for biological applications, for example, as peptide analogues or potential drugs, but also as FRs for polymers . For example, in a patent of Golborn and Duffy, a broad range of aliphatic phosphoramidomethyl phosphonates was introduced.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a new phosphorylated ethylamine, thereon based phosphonamidates and their application as flame retardants

Garth

Klinkowski

Fuhr

et al. 2017

Heteroatom Chemistry

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A new phosphorylated ethylamine salt was synthesized that releases the free amine in situ under water‐free conditions. This storable precursor molecule was used to synthesize a mono‐substituted cyanuric chloride. Further substitutions could not be performed due to the low reactivity of this cyanuric chloride derivative. Also, two novel, bridged phosphonamidates were prepared. Owing to the P‐N synergy, they show enlarged char yields and therefore are promising flame retardants.

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“…The structures have been ordered left-to-right with increasing size: poliovirus 3Dpol (PDB: 1RA6, 461 residues, 52.5 kDa) (Thompson and Peersen, 2004), HCV NS5B (PDB: 5CZB, 563 residues, 62.5 kDa) (Pierra Rouviere et al, 2016), Φ6 P2 (PDB: 1HHS, 664 residues, 74.8 kDa) (Butcher et al, 2001); Φ12 P2 (PDB: 4GZK, 659 residues, 75.3 kDa) (Ren et al, 2013) and rotavirus VP1 (PDB: 2R7Q, 1095 residues, 126.1 kDa) (Lu et al, 2008). The fingers, thumb and palm domains are shown in red, blue, and green, respectively.…”

Section: Figurementioning

confidence: 99%

Cystoviral RNA-directed RNA polymerases: Regulation of RNA synthesis on multiple time and length scales

Alphonse

Ghose

2017

Virus Research

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P2, an RNA-directed RNA polymerase (RdRP), is encoded on the largest of the three segments of the double-stranded RNA genome of cystoviruses. P2 performs the dual tasks of replication and transcription de novo on single-stranded RNA templates, and plays a critical role in the viral life-cycle. Work over the last few decades has yielded a wealth of biochemical and structural information on the functional regulation of P2, on its role in the spatiotemporal regulation of RNA synthesis and its variability across the Cystoviridae family. These range from atomic resolution snapshots of P2 trapped in functionally significant states, in complex with catalytic/structural metal ions, polynucleotide templates and substrate nucleoside triphosphates, to P2 in the context of viral capsids providing structural insight into the assembly of supramolecular complexes and regulatory interactions therein. They include in vitro biochemical studies using P2 purified to homogeneity and in vivo studies utilizing infectious core particles. Recent advances in experimental techniques have also allowed access to the temporal dimension and enabled the characterization of dynamics of P2 on the sub-nanosecond to millisecond timescale through measurements of nuclear spin relaxation in solution and single molecule studies of transcription from seconds to minutes. Below we summarize the most significant results that provide critical insight into the role of P2 in regulating RNA synthesis in cystoviruses.

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Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase

Cited by 12 publications

References 21 publications

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Amide Bond Bioisosteres: Strategies, Synthesis, and Successes

Synthesis of a new phosphorylated ethylamine, thereon based phosphonamidates and their application as flame retardants

Cystoviral RNA-directed RNA polymerases: Regulation of RNA synthesis on multiple time and length scales

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