Interaction of Nevirapine with the Peptide Binding Groove of HLA-DRB1*01:01 and Its Effect on the Conformation of HLA-Peptide Complex

Published on Jun 4, 2018in International Journal of Molecular Sciences5.924
路 DOI :10.3390/IJMS19061660
Makoto Hirasawa5
Estimated H-index: 5
,
Katsunobu Hagihara11
Estimated H-index: 11
+ 2 AuthorsNoriaki Hirayama23
Estimated H-index: 23
(Tokai University)
Sources
Abstract
Human leukocyte antigen (HLA)-DRB1*01:01 has been shown to be involved in nevirapine-induced hepatic hypersensitivity reactions. In the present study, in silico docking simulations and molecular dynamics simulations were performed to predict the interaction mode of nevirapine with the peptide binding groove of HLA-DRB1*01:01 and its possible effect on the position and orientation of the ligand peptide derived from hemagglutinin (HA). In silico analyses suggested that nevirapine interacts with HLA-DRB1*01:01 around the P4 pocket within the peptide binding groove and the HA peptide stably binds on top of nevirapine at the groove. The analyses also showed that binding of nevirapine at the groove will significantly change the inter-helical distances of the groove. An in vitro competitive assay showed that nevirapine (1000 渭M) increases the binding of the HA peptide to HLA-DRB1*01:01 in an allele-specific manner. These results indicate that nevirapine might interact directly with the P4 pocket and modifies its structure, which could change the orientation of loaded peptides and the conformation of HLA-DRB1*01:01; these changes could be distinctively recognized by T-cell receptors. Through this molecular mechanism, nevirapine might stimulate the immune system, resulting in hepatic hypersensitivity reactions.
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References28
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#1Rebecca Pavlos (Murdoch University)H-Index: 16
#2Elizabeth McKinnon (Murdoch University)H-Index: 26
Last. Elizabeth J. Phillips (Murdoch University)H-Index: 64
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Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-...
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#1Makoto HirasawaH-Index: 5
#2Katsunobu HagiharaH-Index: 11
Last. Noriaki Hirayama (Tokai University)H-Index: 23
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Idiosyncratic ximelagatran-induced hepatotoxicity has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01 and ximelagatran has been reported to inhibit the binding of the ligand peptide to HLA-DRB1*07:01 in vitro. In order to predict the possible interaction modes of ximelagatran with HLA-DR molecules, in silico docking simulations were performed. Molecular dynamics (MD) simulations were also performed to predict the effect of ximelagatran on the binding mode of the liga...
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#1Daniel F. Carr (University of Liverpool)H-Index: 23
#2Stephane Bourgeois (QMUL: Queen Mary University of London)H-Index: 15
Last. Sam Haldenby (University of Liverpool)H-Index: 17
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BACKGROUND: The antiretroviral nevirapine is associated with hypersensitivity reactions in 6%-10% of patients, including hepatotoxicity, maculopapular exanthema, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). OBJECTIVES: To undertake a genome-wide association study (GWAS) to identify genetic predisposing factors for the different clinical phenotypes associated with nevirapine hypersensitivity. METHODS: A GWAS was undertaken in a discovery cohort of 151 nevirapine-hypersensi...
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#1Makoto Osabe (Nagoya City University)H-Index: 2
#2Masahiro Tohkin (Nagoya City University)H-Index: 13
Last. Noriaki Hirayama (Tokai University)H-Index: 23
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#1Makoto Hirasawa (Daiichi Sankyo)H-Index: 5
#2Katsunobu Hagihara (Daiichi Sankyo)H-Index: 11
Last. Takashi Izumi (Daiichi Sankyo)H-Index: 17
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Idiosyncratic lapatinib-induced liver injury has been reported to be associated with human leukocyte antigen (HLA)-DRB1*07:01. In order to investigate its mechanism, interaction of lapatinib with HLA-DRB1*07:01 and its ligand peptide derived from tetanus toxoid, has been evaluated in vitro. Here we show that lapatinib enhances binding of the ligand peptide to HLA-DRB1*07:01. Furthermore in silico molecular dynamics analysis revealed that lapatinib could change the 尾 chain helix in the HLA-DRB1*0...
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#1Elena M. Cornejo Castro (University of Liverpool)H-Index: 9
#2Daniel F. CarrH-Index: 23
Last. Munir PirmohamedH-Index: 114
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Abstract Various studies have investigated associations between immunogenetic (HLA-allelotypes) factors and the risk of nevirapine-induced hypersensitivity reactions. However, results from individual studies have been inconsistent. To evaluate the association between HLA alleles and nevirapine hypersensitivity, a systematic review and meta-analysis was carried out. A literature review of articles published up to December 2014 was performed. Where both allelotype and phenotype data from two or mo...
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#1Marharyta Petukh (Clemson University)H-Index: 15
#2Bohua Wu (Clemson University)H-Index: 2
Last. Emil Alexov (Clemson University)H-Index: 53
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Chronic Beryllium (Be) Disease (CBD) is a granulomatous disorder that predominantly affects the lung. The CBD is caused by Be exposure of individuals carrying the HLA-DP2 protein of the major histocompatibility complex class II (MHCII). While the involvement of Be in the development of CBD is obvious and the binding site and the sequence of Be and peptide binding were recently experimentally revealed [1], the interplay between induced conformational changes and the changes of the peptide binding...
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#1Niamh M. Keane (PMH: Princess Margaret Hospital for Children)H-Index: 17
#2Rebecca PavlosH-Index: 16
Last. Elizabeth J. PhillipsH-Index: 64
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Objectives: This study sought to examine nevirapine hypersensitivity (NVP HSR) phenotypes and their relationship with differing major histocompatibility complex (MHC) Class I and Class II alleles and the associated CD4+ and CD8+ T-cell NVP-specific responses and their durability over time. Methods: A retrospective cohort study compared HIV-positive patients with NVP HSR, defined by fever and hepatitis and/or rash, with those tolerant of NVP for more than 3 months. Covariates included class I (HL...
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#1Gina M. Clayton (University of Colorado Denver)H-Index: 4
#2Yang Wang (University of Colorado Denver)H-Index: 12
Last. John W. KapplerH-Index: 137
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Summary T-cell-mediated hypersensitivity to metal cations is common in humans. How the T聽cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T聽cells to inhaled beryllium. Here, we show that the T聽cell ligand is created when a Be 2+ cation bec...
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#1Daniel F. Carr (University of Liverpool)H-Index: 23
#2Mas Chaponda (University of Liverpool)H-Index: 13
Last. Munir Pirmohamed (University of Liverpool)H-Index: 114
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Background. The nonnucleoside reverse transcriptase inhibitor nevirapine is the cornerstone of treatment for human immunodeficiency virus (HIV) in many sub-Saharan African countries. However, nevirapine is associated with a 6%鈥10% risk of developing a hypersensitivity reaction, with different phenotypes, including the blistering conditions Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Our aim was to identify predictive human leukocyte antigen (HLA) markers that are associa...
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Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the ada...
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#1Aline T. Marinho (NOVA: Universidade Nova de Lisboa)H-Index: 8
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AbstractNevirapine (NVP) is a first-generation non-nucleoside reverse transcriptase inhibitor widely used for the treatment and prophylaxis of human immunodeficiency virus infection. The drug is taken throughout the patient鈥檚 life and, due to the availability of an extended-release formulation, it is administered once daily. This antiretroviral is one of the scarce examples of drugs with prescription criteria based on sex, in order to prevent adverse reactions. The therapy with NVP has been asso...
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#1Volker M. Lauschke (KI: Karolinska Institutet)H-Index: 33
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Abstract Individuals differ substantially in their response to pharmacological treatment. Personalized medicine aspires to embrace these inter-individual differences and customize therapy by taking a wealth of patient-specific data into account. Pharmacogenomic constitutes a cornerstone of personalized medicine that provides therapeutic guidance based on the genomic profile of a given patient. Pharmacogenomics already has applications in the clinics, particularly in oncology, whereas future deve...
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The current Special Issue is devoted to the broad spectrum of hepatotoxicity with its molecular mechanisms and pathophysiology, presented in eight publications [...]
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