The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome

Abstract Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reaction...

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Autores principales:	James Fodor, Blake T. Riley, Itamar Kass, Ashley M. Buckle, Natalie A. Borg
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2019
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6786753185214d0691d8d5644bacc65a
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spelling	oai:doaj.org-article:6786753185214d0691d8d5644bacc65a2021-12-02T15:08:21ZThe Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome10.1038/s41598-019-47001-12045-2322https://doaj.org/article/6786753185214d0691d8d5644bacc65a2019-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-019-47001-1https://doaj.org/toc/2045-2322Abstract Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B57:01+ HIV patients whilst retaining potent antiretroviral activity.James FodorBlake T. RileyItamar KassAshley M. BuckleNatalie A. BorgNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 9, Iss 1, Pp 1-11 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q James Fodor Blake T. Riley Itamar Kass Ashley M. Buckle Natalie A. Borg The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
description	Abstract Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B57:01+ HIV patients whilst retaining potent antiretroviral activity.
format	article
author	James Fodor Blake T. Riley Itamar Kass Ashley M. Buckle Natalie A. Borg
author_facet	James Fodor Blake T. Riley Itamar Kass Ashley M. Buckle Natalie A. Borg
author_sort	James Fodor
title	The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
title_short	The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
title_full	The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
title_fullStr	The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
title_full_unstemmed	The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
title_sort	role of conformational dynamics in abacavir-induced hypersensitivity syndrome
publisher	Nature Portfolio
publishDate	2019
url	https://doaj.org/article/6786753185214d0691d8d5644bacc65a
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The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome

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