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Towards depersonalized abacavir therapy: chemical modification eliminates HLA-B*57 : 01-restricted CD8+ T-cell
Dean J Naisbitt1, Emma L Yang, Mohammad Alhaidari
1aMRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology bDepartment of Chemistry, University of Liverpool, Liverpool, England cLaboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Maryland, USA dDrug Metabolism and Pharmacokinetics, GlaxoSmithKline, Hertfordshire, England.
Objective:
Exposure to abacavir is associated with T-cell-mediated hypersensitivity reactions in individuals carrying human leukocyte antigen (HLA)-B57 : 01. To activate T cells, abacavir interacts directly with endogenous HLA-B57 : 01 and HLA-B57 : 01 expressed on the surface of antigen presenting cells. We have investigated whether chemical modification of abacavir can produce a molecule with antiviral activity that does not bind to HLA-B57 : 01 and activate T cells.
Design:
An interdisciplinary laboratory study using samples from human donors expressing HLA-B57 : 01. Researchers were blinded to the analogue structures and modelling data.
Methods:
Sixteen 6-amino substituted abacavir analogues were synthesized. Computational docking studies were completed to predict capacity for analogue binding within HLA-B57 : 01. Abacavir-responsive CD8 clones were generated to study the association between HLA-B57 : 01 analogue binding and T-cell activation. Antiviral activity and the direct inhibitory effect of analogues on proliferation were assessed.
Results:
Major histocompatibility complex class I-restricted CD8 clones proliferated and secreted IFNγ following abacavir binding to surface and endogenous HLA-B57 : 01. Several analogues retained antiviral activity and showed no overt inhibitory effect on proliferation, but displayed highly divergent antigen-driven T-cell responses. For example, abacavir and N-propyl abacavir were equally potent at activating clones, whereas the closely related analogues N-isopropyl and N-methyl isopropyl abacavir were devoid of T-cell activity. Docking abacavir analogues to HLA-B57 : 01 revealed a quantitative relationship between drug-protein binding and the T-cell response.
Conclusion:
These studies demonstrate that the unwanted T-cell activity of abacavir can be eliminated whilst maintaining the favourable antiviral profile. The in-silico model provides a tool to aid the design of safer antiviral agents that may not require a personalized medicines approach to therapy.
