Identifying Specific Conformations by Using a Carbohydrate Scaffold: Discovery of Subtype-Selective LPA-Receptor Agonists and an Antagonist

摘要

Lysophosphatidic acids (LPA) are a group of important extracellular signaling molecules that elicit a wide variety of fundamental biological responses, such as cell-growth stimulation, calcium mobilization, escape from apoptosis, tumor-cell invasion, and smooth-muscle contraction. The diverse properties are mediated through interactions of LPA with G-protein-coupled receptors named LPA_1, LPA_2, and LPA_3. Studies to explore the specific role of each subtype are in progress, and are essential for further advances, for example, for designing drugs to modulate a specific LPA-mediated signal-transduction pathway. Studies with subtype-selective agonists and antagonists are very powerful for this purpose. Herein, we describe a new strategy for the discovery of subtype-selective ligands for LPA receptors, based on the identification of specific active conformations of LPA by using carbohydrates as scaffolds.