Modification of the cyclopropyl moiety of abacavir provides insight into the structure activity relationship between HLA‐B*57:01 binding and T‐cell activation

Thomson, Paul J ORCID: 0000-0001-5431-0459, Illing, Patricia T, Farrell, John ORCID: 0000-0002-8726-5997, Alhaidari, Mohammad, Bell, Catherine C, Berry, Neil ORCID: 0000-0003-1928-0738, O'Neill, Paul M, Purcell, Anthony W, Park, Kevin B and Naisbitt, Dean J (2020) 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). pp. 636-647.

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Abstract

Background Abacavir is associated with hypersensitivity reactions in individuals positive for the HLA‐B*57:01 allele. The drug binds within the peptide binding groove of HLA‐B*57:01 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*57:01 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*57:01 peptide binding groove. In parallel, the effect of selected abacavir analogues on the repertoire of self‐peptides presented by cellular HLA‐B*57:01 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*57:01 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*57:01. 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*57:01 binding and peptide display by antigen presenting cells relate to the activation of CD8+ T‐cells.

Item Type:	Article
Uncontrolled Keywords:	drug hypersensitivity, HLA, human, mass spectrometry, T-cells
Depositing User:	Symplectic Admin
Date Deposited:	30 Oct 2019 08:58
Last Modified:	19 Jan 2023 00:21
DOI:	10.1111/all.14057
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3059879