CHAPTER 13. Small Molecule Modulators of Endo-lysosomal Toll-like Receptors

TLRs are germline-encoded pattern recognition receptors and are a critical first line of defense for self–nonself discrimination by the host immune response. The major group of TLRs (TLR1, 2, 4, 5, 6 and 10) is expressed on the cell surface and recognizes lipids, lipopeptides and proteins. Another group of TLRs (TLR3, 7, 8, 9) is expressed in the endosomal compartments, instead of the cell surface, and recognizes pathogen-derived nucleic acids. This chapter mainly focuses on the endo-lysosomal TLRs. It describes the structural components of TLRs and their modulation through specific ligands with respect to agonists and antagonists. The efforts toward the development of specific small molecule agonists and antagonists for the endo-lysosomal TLRs, which play an important role in different clinical contexts, have been depicted. Agonists have the ability to bind and function as immune response enhancers, whereas antagonists have the ability to block the response generated by the action of agonists and can stop aberrant activation of immune responses. Agonists have been extensively explored as useful therapeutic agents as well as adjuvants in cancer and infectious diseases. Antagonists have a therapeutic role in suppressing the overactive immune response in chronic inflammatory and autoimmune disorders.