PMID- 31324847
OWN - NLM
STAT- MEDLINE
DCOM- 20201102
LR  - 20210110
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 9
IP  - 1
DP  - 2019 Jul 19
TI  - The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity 
      Syndrome.
PG  - 10523
LID - 10.1038/s41598-019-47001-1 [doi]
LID - 10523
AB  - 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)-B*57:01, but not patients carrying closely related 
      alleles. Abacavir's specificity to HLA-B*57:01 is attributed to its binding site 
      within the peptide-binding cleft and subsequent influence of the repertoire of 
      peptides that can bind HLA-B*57:01. To further our understanding of 
      abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the 
      dynamics of three different peptides bound to HLA-B*57:01 in the presence and 
      absence of abacavir or abacavir analogues. We found that abacavir and associated 
      peptides bind to HLA-B*57:01 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-B*57:01+ HIV patients whilst retaining 
      potent antiretroviral activity.
FAU - Fodor, James
AU  - Fodor J
AD  - Department of Biochemistry and Molecular Biology, Biomedicine Discovery 
      Institute, Monash University, Clayton, Victoria, 3800, Australia.
FAU - Riley, Blake T
AU  - Riley BT
AUID- ORCID: 0000-0003-2176-0503
AD  - Department of Biochemistry and Molecular Biology, Biomedicine Discovery 
      Institute, Monash University, Clayton, Victoria, 3800, Australia.
FAU - Kass, Itamar
AU  - Kass I
AUID- ORCID: 0000-0002-5368-937X
AD  - Department of Biochemistry and Molecular Biology, Biomedicine Discovery 
      Institute, Monash University, Clayton, Victoria, 3800, Australia.
AD  - The National Institute for Biotechnology in the Negev, Ben-Gurion University of 
      the Negev, Beer-Sheva, 8410501, Israel.
FAU - Buckle, Ashley M
AU  - Buckle AM
AUID- ORCID: 0000-0003-2943-9044
AD  - Department of Biochemistry and Molecular Biology, Biomedicine Discovery 
      Institute, Monash University, Clayton, Victoria, 3800, Australia. 
      ashley.buckle@monash.edu.
FAU - Borg, Natalie A
AU  - Borg NA
AUID- ORCID: 0000-0002-8677-9056
AD  - Department of Biochemistry and Molecular Biology, Biomedicine Discovery 
      Institute, Monash University, Clayton, Victoria, 3800, Australia. 
      natalie.borg@monash.edu.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190719
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Anti-HIV Agents)
RN  - 0 (Dideoxynucleosides)
RN  - 0 (HLA-B Antigens)
RN  - 0 (HLA-B*57:01 antigen)
RN  - 0 (Oligopeptides)
RN  - WR2TIP26VS (abacavir)
SB  - IM
MH  - Amino Acid Sequence
MH  - Anti-HIV Agents/*adverse effects/metabolism/pharmacology
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Dideoxynucleosides/*adverse effects/metabolism/pharmacology
MH  - Drug Hypersensitivity/*etiology/genetics
MH  - Genetic Predisposition to Disease
MH  - HLA-B Antigens/drug effects/*metabolism
MH  - Humans
MH  - Models, Molecular
MH  - Molecular Dynamics Simulation
MH  - Oligopeptides/metabolism
MH  - Protein Binding
MH  - Protein Conformation/drug effects
PMC - PMC6642150
COIS- The authors declare no competing interests.
EDAT- 2019/07/22 06:00
MHDA- 2020/11/03 06:00
PMCR- 2019/07/19
CRDT- 2019/07/21 06:00
PHST- 2019/02/26 00:00 [received]
PHST- 2019/07/04 00:00 [accepted]
PHST- 2019/07/21 06:00 [entrez]
PHST- 2019/07/22 06:00 [pubmed]
PHST- 2020/11/03 06:00 [medline]
PHST- 2019/07/19 00:00 [pmc-release]
AID - 10.1038/s41598-019-47001-1 [pii]
AID - 47001 [pii]
AID - 10.1038/s41598-019-47001-1 [doi]
PST - epublish
SO  - Sci Rep. 2019 Jul 19;9(1):10523. doi: 10.1038/s41598-019-47001-1.