Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA-B*57:01 binding and T-cell activation.
Allergy
; 75(3): 636-647, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31549414
ABSTRACT
BACKGROUND:
Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA-B*5701 allele. The drug binds within the peptide binding groove of HLA-B*5701 altering peptides displayed on the cell surface. Presentation of these HLA-abacavir-peptide complexes to T-cells is hypothesized to trigger a CD8+ T-cell response underpinning the hypersensitivity. Thus, the aim of this study was to explore the relationship between the structure of abacavir with HLA-B*5701 binding and the CD8+ T-cell activation.METHODS:
Seventeen abacavir analogues were synthesized and cytokine secretion from abacavir/abacavir analogue-responsive CD8+ T-cell clones was measured using IFN-γ ELIspot. In silico docking studies were undertaken to assess the predicted binding poses of the abacavir analogues within the HLA-B*5701 peptide binding groove. In parallel, the effect of selected abacavir analogues on the repertoire of self-peptides presented by cellular HLA-B*5701 was characterized using mass spectrometry.RESULTS:
Abacavir and ten analogues stimulated CD8+ T-cell IFN-γ release. Molecular docking of analogues that retained antiviral activity demonstrated a relationship between predicted HLA-B*5701 binding orientations and the ability to induce a T-cell response. Analogues that stimulated T-cells displayed a perturbation of the natural peptides displayed by HLA-B*5701. The antigen-specific CD8+ T-cell response was dependent on the enantiomeric form of abacavir at both cyclopropyl and cyclopentyl regions.CONCLUSION:
Alteration of the chemical constitution of abacavir generates analogues that retain a degree of pharmacological activity, but have variable ability to activate T-cells. Modelling and immunopeptidome analysis delineate how drug HLA-B*5701 binding and peptide display by antigen presenting cells relate to the activation of CD8+ T-cells.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T CD8-Positivos
/
Hipersensibilidade a Drogas
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article