Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease

Nagpal, Neha; Goyal, Sukriti; Wahi, Divya; Jain, Ritu; Jamal, Salma; Singh, Aditi; Rana, Preeti; Grover, Abhinav

doi:10.1016/j.gene.2015.06.008

Cited by 17 publications

(9 citation statements)

References 31 publications

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“…[ Plaza et al [2012]; Bartels et al [2013]; Karino et al [2013]; Bartolini et al [2015]; Beloukas et al [2015]; Cuypers et al [2015];Nagpal et al [2015]; Premoli and Aghemo, [2015]; Sarrazin, [2015] A30K Aissa Larousse et al [2015] (Continued) information and/or for a more effective oncoming antiviral treatment may be a rational choice. Instead, in patients with cirrhosis or with other urgencies requiring early treatment, the tests to detect NS3 and NS5A mutations should be performed quickly to identify an effective treatment.…”

Section: Ns5a Inhibitorsmentioning

confidence: 99%

Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

Coppola

Minichini

Starace

et al. 2016

Journal of Medical Virology

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Introduced in 2013-2014, the second- and third-wave directly acting antivirals (DAAs) have strongly enhanced the efficacy and tolerability of anti-HCV treatment, with a sustained virological response (SVR) in 90-95% of cases treated. The majority of patients who did not achieve an SVR were found to be infected with HCV strains with a reduced susceptibility to these drugs. Indeed, the high error rate of the viral polymerase and a fast virion production (100-fold higher than the human immunodeficiency virus) result in a mixture of viral genetic populations (quasi-species) pre-existing treatment initiation. These mutants occur frequently in the NS5A region, with a moderate frequency in the NS3/4A region and rarely in the NS5B region. Treatment-induced resistant mutants to NS5A DAAs persist for years after treatment discontinuation, whereas those resistant to the NS3 DAAs have a shorter duration. This review focuses on the type and prevalence of viral strains with a reduced sensitivity to DAAs, their clinical impact and influence on the response to treatment and, consequently, on treatment choice for DAA-experienced patients. J. Med. Virol. 88:1659-1671, 2016. © 2016 Wiley Periodicals, Inc.

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Section: Ns5a Inhibitorsmentioning

confidence: 99%

Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

Coppola

Minichini

Starace

et al. 2016

Journal of Medical Virology

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“…Although standard combined therapy of pegylated-IFNα and ribavirin (RBV) have had some success, there has been much greater clinical response when treating HCV + patients with newly FDA-approved NS3/4A protease inhibitors boceprevir, telaprevir, and simeprevir [15-17]. Despite this recent success, the rapidly mutating HCV genome can generate drug resistant variants which might lead to virologic breakthrough or relapse [18-20]. Moreover, many patients who may be cured of HCV infection by these novel drugs may have already developed associated disease or malignancies that cannot be treated effectively by these anti-viral agents.…”

Section: Introductionmentioning

confidence: 99%

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

Spear

Callender

Roszkowski

et al. 2016

Cancer Immunol Immunother

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The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease is highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

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“…The protein preprocessing steps included adjustment of bond orders, cofactors and metal ions, assignment of correct formal charges, hydrogen bonds addition and protein termini capping followed by a restrained energy minimization of the protein. A receptor grid was generated centered on the active site residues provided by the user using the Receptor Grid Generation panel of Schrodinger [ 54 , 55 ]. The 37 Alzheimer specific drugs were used as ligands and were prepared using the LigPrep [ 56 ] program available from Schrodinger.…”

Section: Methodsmentioning

confidence: 99%

Integrating network, sequence and functional features using machine learning approaches towards identification of novel Alzheimer genes

et al. 2016

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BackgroundAlzheimer’s disease (AD) is a complex progressive neurodegenerative disorder commonly characterized by short term memory loss. Presently no effective therapeutic treatments exist that can completely cure this disease. The cause of Alzheimer’s is still unclear, however one of the other major factors involved in AD pathogenesis are the genetic factors and around 70 % risk of the disease is assumed to be due to the large number of genes involved. Although genetic association studies have revealed a number of potential AD susceptibility genes, there still exists a need for identification of unidentified AD-associated genes and therapeutic targets to have better understanding of the disease-causing mechanisms of Alzheimer’s towards development of effective AD therapeutics.ResultsIn the present study, we have used machine learning approach to identify candidate AD associated genes by integrating topological properties of the genes from the protein-protein interaction networks, sequence features and functional annotations. We also used molecular docking approach and screened already known anti-Alzheimer drugs against the novel predicted probable targets of AD and observed that an investigational drug, AL-108, had high affinity for majority of the possible therapeutic targets. Furthermore, we performed molecular dynamics simulations and MM/GBSA calculations on the docked complexes to validate our preliminary findings.ConclusionsTo the best of our knowledge, this is the first comprehensive study of its kind for identification of putative Alzheimer-associated genes using machine learning approaches and we propose that such computational studies can improve our understanding on the core etiology of AD which could lead to the development of effective anti-Alzheimer drugs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3108-1) contains supplementary material, which is available to authorized users.

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Molecular principles behind Boceprevir resistance due to mutations in hepatitis C NS3/4A protease

Cited by 17 publications

References 31 publications

Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

Clinical impact of the hepatitis C virus mutations in the era of directly acting antivirals

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors

Integrating network, sequence and functional features using machine learning approaches towards identification of novel Alzheimer genes

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