Diphenylcarboxamides as Inhibitors of HCV Non-Structural Protein NS5a

Carter, Malcolm; Baxter, Bob; Bushnell, David J.; Cockerill, Stuart; Chapman, Jo; Fram, Sally; Goulding, Emma; Lockyer, Mike; Mathews, Neil; Najarro, Pilar; Rupassara, Dilupa; Salter, James; Thomas, Elaine R.; Wheelhouse, Chris; Borger, Jessica G.; Powell, Kenneth L.

doi:10.1016/j.antiviral.2010.02.331

Cited by 2 publications

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“…Mechanism of action studies have revealed that a number of mutants conferring resistance against both BMS-790052 and AZD7295 mapped to the NS5A region of the viral genome 6 27 28 29 . Two of the most common mutation sites are Y93H/N/C and L31V/M/F which confer 19- to 47,000-fold and 23- to 3,350-fold resistance against BMS-790052, respectively 4 6 .…”

Section: Resultsmentioning

confidence: 99%

Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA

Ascher

Wielens

Nero

et al. 2014

Sci Rep

109

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Hepatitis C virus (HCV) infection affects more than 170 million people. The high genetic variability of HCV and the rapid development of drug-resistant strains are driving the urgent search for new direct-acting antiviral agents. A new class of agents has recently been developed that are believed to target the HCV protein NS5A although precisely where they interact and how they affect function is unknown. Here we describe an in vitro assay based on microscale thermophoresis and demonstrate that two clinically relevant inhibitors bind tightly to NS5A domain 1 and inhibit RNA binding. Conversely, RNA binding inhibits compound binding. The compounds bind more weakly to known resistance mutants L31V and Y93H. The compounds do not affect NS5A dimerisation. We propose that current NS5A inhibitors act by favouring a dimeric structure of NS5A that does not bind RNA.

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Section: Resultsmentioning

confidence: 99%

Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA

Ascher

Wielens

Nero

et al. 2014

Sci Rep

109

View full text Add to dashboard Cite

show abstract

“…This drug discovery program aimed at inhibitors of HCV NS5A is certainly an excellent example of increased willingness of drug companies to invest in higher risk efforts to validate new targets. Other HCV NS5A inhibitors have been reported,15, 16 but BMS‐790052 is apparently the most advanced in the clinic. The method of its development—employing high‐throughput screening of drug libraries in cell‐based replicon assays—is also significant as a model for others to follow in the discovery of drugs operating by unconventional mechanisms.…”

Section: Half‐maximum Effective Concentrations (Ec50) For Inhibition mentioning

confidence: 99%

Drugs for Hepatitis C: Unlocking a New Mechanism of Action

Bell¹

2010

ChemMedChem

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Aggregation of the human peptide amyloid‐β (Aβ) is a key event in Alzheimer's disease (AD). Zinc ions play an important role in AD and in Aβ aggregation. In vitro, ZnII binds to Aβ and accelerates its aggregation. In this work we have investigated ZnII binding to the synthetic peptide Aβ1–16, which contains the metal‐binding domain of Aβ. CdII was used to probe the ZnII site. Aβ1–16 bound one equivalent of ZnII with an apparent dissociation constant (Kd) of 10−4 M. This Kd value is in the same range as the Zn concentration needed to precipitate Aβ. Circular dichroism and NMR indicated predominantly random‐coil secondary structures of apo‐Aβ1–16, ZnII–Aβ1–16 and CdII–Aβ1–16, which were all highly dynamic and flexible. The three histidines at positions 6, 13 and 14 were suggested to be ligands to ZnII and CdII. Evidence that the aspartate at position 1 served as a fourth ligand to ZnII and CdII was found at pH 8.7. 111CdII NMR showed a resonance at 84 ppm, in line with a mixed oxygen‐/nitrogen‐ligand environment. The tyrosine at position 10 could be excluded as a ligand.

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Diphenylcarboxamides as Inhibitors of HCV Non-Structural Protein NS5a

Cited by 2 publications

References 0 publications

Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA

Potent hepatitis C inhibitors bind directly to NS5A and reduce its affinity for RNA

Drugs for Hepatitis C: Unlocking a New Mechanism of Action

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