5th World Congress on Virology
University of Alberta,Canada
Title: Rational Design Of Immune Checkpoints’ Small Molecule Inhibitors
Biography: Khaled Barakat
T lymphocytes preserve the immunological balance between defending against viral infection and preventing continual activated immune responses. While T cells’ specificity against cancer or viral infection is determined by the interaction between the T-cell receptor complex (TCR) and antigenic peptides bound in surface major histocompatibility complex (MHC) molecules, the full activation of T cells requires a second signal obtained by the binding of the co-receptor CD28 on T cells to CD80/86 molecules on activated antigen presenting cells (APCs). Once mobilized, T cells also express other receptors that inhibit their proliferation and cytokine production, known as immune checkpoints. Among these receptors are Cytotoxic T Lymphocyte Antigen-4 (CTLA-4), programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) and many others. Blocking the interactions between these receptors and their ligands emerged as a ‘game changer’ in immunotherapy, with antibodies directed toward PD-1, for example, being selected as ‘drug of the year’ for 2013 by Science. More importantly, combination blockage of multiple co-inhibitory pathways has a greater efficacy by preventing accumulation of the unblocked negative co-receptor, allowing T cells to continue to survive, proliferate, and carry out effector functions within infected cells. This talk will focus on PD-1 and will describe for the first time two accurate models for human PD-1 bound to its two human ligands. The talk will also demonstrate how these two models are being used to rationally design small molecule inhibitors for the Pd-1 pathway.
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