Induced‐Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target

Cummings, Maxwell D.; Lindberg, Jimmy; Lin, Tse‐I; Kock, Herman de; Lenz, Oliver; Lilja, Elisabet; Felländer, Sara; Baraznenok, Vera; Nyström, Staffan; Nilsson, Magnus; Vrang, Lotta; Edlund, Michael; Rosenquist, Åsa; Samuelsson, Bertil; Raboisson, Pierre; Simmen, Kenneth

doi:10.1002/ange.200906696

Cited by 23 publications

(45 citation statements)

References 30 publications

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“…Four of the seven patients and both patients with baseline I132L and D168E polymorphism, respectively, achieved SVR12. The amino acid I132L forms part of the hydrophobic surface in the S1/S3 pocket that binds the P1/P3 part of the simeprevir macrocycle …”

Section: Discussionmentioning

confidence: 99%

“…In HCV genotype 4‐infected patients, treatment failure was associated with emerging mutations at one or more of the NS3 amino acid positions 80, 122, 155, 156 and/or 168: mainly D168V and D168E alone or combined with mutations at position 80 and mutations at position 155 . Amino acid residues at these positions are contributing to the binding surface in an extended S2 subsite induced by simeprevir binding . However, amino acid mixtures were more frequently observed at time of failure at these positions in genotype 4 than in genotype 1, potentially suggesting a larger quasi‐species diversity in genotype 4 present at failure …”

Section: Discussionmentioning

confidence: 99%

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Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

Fevery

Verbinnen

Peeters

et al. 2016

Journal of Viral Hepatitis

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Simeprevir is a hepatitis C virus NS3/4A protease inhibitor. Hepatitis C virus baseline NS3/4A polymorphisms and emerging mutations were characterized in treatment-naїve and treatment-experienced genotype 4-infected patients treated with simeprevir+peginterferon/ribavirin in the RESTORE study. Population sequencing of the NS3/4A region was performed and in vitro simeprevir activity against site-directed mutants or chimeric replicons with patient-derived NS3 protease sequences was assessed in a transient replicon assay. Simeprevir remained active against most (83/91 [91%]) baseline isolates tested in the chimeric replicon assay. Eight baseline isolates reduced simeprevir activity; these carried I132L or D168E substitutions reducing simeprevir median activity by 4.6- and 39-fold, respectively. Six of these eight isolates were from patients achieving sustained virologic response. Baseline NS3 Q80K polymorphism was not observed in the genotype 4-infected patients. Of the 107 simeprevir-treated patients, 37 did not achieve sustained virologic response for any reason. Of the 32 patients who failed treatment and had sequencing information, 28 (88%) had emerging mutations at NS3 positions 80, 122, 155, 156 and/or 168 at time of failure, similar to those in genotype 1. Emerging mutations were mainly D168V and D168E alone or combined with mutations at position 80. In general, isolates obtained at time of failure displayed high-level in vitro resistance to simeprevir (fold change ≥50) in a chimeric replicon assay with a median simeprevir fold change value of 440, consistent with observed mutations. In conclusion, emerging mutations in genotype 4 patients failing simeprevir+peginterferon/ribavirin treatment were similar to those in genotype 1 and conferred high-level resistance to simeprevir.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

Fevery

Verbinnen

Peeters

et al. 2016

Journal of Viral Hepatitis

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“…Crystal structures of the four protease-peptide complexes, fourteen protein-recognition domains, and three protease apo structures were procured from the Protein Data Bank (PDB) (S1 Table) [27,37,42,51–65]. Structures were filtered for a resolution equal to or lower than 2.8 Å and a bound peptide or peptidomimetic inhibitor.…”

Section: Methodsmentioning

confidence: 99%

MFPred: Rapid and accurate prediction of protein-peptide recognition multispecificity using self-consistent mean field theory

2017

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Multispecificity–the ability of a single receptor protein molecule to interact with multiple substrates–is a hallmark of molecular recognition at protein-protein and protein-peptide interfaces, including enzyme-substrate complexes. The ability to perform structure-based prediction of multispecificity would aid in the identification of novel enzyme substrates, protein interaction partners, and enable design of novel enzymes targeted towards alternative substrates. The relatively slow speed of current biophysical, structure-based methods limits their use for prediction and, especially, design of multispecificity. Here, we develop a rapid, flexible-backbone self-consistent mean field theory-based technique, MFPred, for multispecificity modeling at protein-peptide interfaces. We benchmark our method by predicting experimentally determined peptide specificity profiles for a range of receptors: protease and kinase enzymes, and protein recognition modules including SH2, SH3, MHC Class I and PDZ domains. We observe robust recapitulation of known specificities for all receptor-peptide complexes, and comparison with other methods shows that MFPred results in equivalent or better prediction accuracy with a ~10-1000-fold decrease in computational expense. We find that modeling bound peptide backbone flexibility is key to the observed accuracy of the method. We used MFPred for predicting with high accuracy the impact of receptor-side mutations on experimentally determined multispecificity of a protease enzyme. Our approach should enable the design of a wide range of altered receptor proteins with programmed multispecificities.

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“…TMC435 (TMC435350) is a macrocyclic noncovalent inhibitor of the HCV NS3/4A protease . It has been selected as the clinical drug candidate from a series of cyclopentane‐containing macrocyclic PIs .…”

Section: Protease (Ns3/4a) Inhibitors Other Than Telaprevir and Bocepmentioning

confidence: 99%

“…Narlaprevir effected a robust HCV RNA decline and high SVR rates when followed by SOC in both treatment-experienced and treatmentnaïve HCV genotype 1-infected patients [69]. TMC435 (TMC435350) is a macrocyclic noncovalent inhibitor of the HCV NS3/4A protease [70]. It has been selected as the clinical drug candidate from a series of cyclopentane-containing macrocyclic PIs [71].…”

Section: Proteasementioning

confidence: 99%

The race for interferon‐free HCV therapies: a snapshot by the spring of 2012

Clercq

2012

Reviews in Medical Virology

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After a decade of having been the standard of care (SOC) for the treatment of chronic HCV infection, PEGylated IFN (combined with ribavirin) is now at the verge of being complemented and then replaced by a combination of new DAAs and even some compounds interacting with host cell factors. Principal targets for the direct-acting antivirals (DAAs) are the protease NS3/4A, the protein NS5A, and the RNA-dependent RNA polymerase NS5B, which offers at least two target sites, the catalytic domain for nucleos(t)ides and several non-catalytic (allosteric) domains for the non-nucleoside type of NS5B inhibitors. Two PIs have already been approved, but many more NS3/4A, NS5A, and NS5B (up to 40!) inhibitors are in (pre)clinical development. The abundance of candidate anti-HCV drugs will, on the one hand, speed up their development but, on the other hand, complicate the choice of the most appropriate drug combination(s).

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Induced‐Fit Binding of the Macrocyclic Noncovalent Inhibitor TMC435 to its HCV NS3/NS4A Protease Target

Cited by 23 publications

References 30 publications

Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

Virology analyses of HCV genotype 4 isolates from patients treated with simeprevir and peginterferon/ribavirin in the Phase III RESTORE study

MFPred: Rapid and accurate prediction of protein-peptide recognition multispecificity using self-consistent mean field theory

The race for interferon‐free HCV therapies: a snapshot by the spring of 2012

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