Vaccine Adjuvants: From Empirical to a More Rational Drug Design

Like other drugs, adjuvants are ligands with distinct structures that interact with specific cell receptors, modulating the immune response. This definition excludes formulations and delivery systems. New adjuvants may be discovered using methods based on a ligand and its receptor's structural and functional traits, a process known as rational drug design. This strategy requires detailed information about both the receptors and their ligands. Such information is obtained using techniques like X-ray crystallography and 2D-nuclear magnetic resonance (NMR) to establish the spatial interactions between a ligand's functional groups and its receptor. This data is necessary to establish reliable structure-activity relationships, which, when applied to computer-aided drug design, facilitate the creation of better adjuvants as an empirical strategy. Since Quillaja saponin adjuvants likely act separately on innate and adaptive immune cells via specific functional groups and unidentified cell receptors, it is crucial to identify these receptors. This task may be achieved using bioorthogonal chemistry and proteomic methods to identify and isolate the receptors. Initially focusing on those unidentified receptors where chemical modifications of these glycosides, such as the aldehyde group and fucose residue, cause drastic changes in adjuvanticity. The isolated receptor(s) can then be characterized by X-ray crystallography and/or 2D-NMR; this information can be applied to computer-aided drug design to rationally design new derivatives. This methodology will prevent the proposition of dubious structure-activity relationships based on incomplete immunological data, unknown receptors, and unsuspected physical factors, providing essential information for designing new adjuvants and elucidating these compounds' mechanisms of action.