Structural Biology of Chronic Inflammation-Associated Signalling Pathways: Toward Structure-Guided Drug Development

Abstract

Chronic inflammation is involved in the provocation, progression, and exacerbation of various diseases, such as cancer and fibrosis. To treat these diseases , it is essential to understand their pathogenesis and develop therapeutic compounds that target the underlying signalling pathways. Recent technical advances in structural biology have enabled us to determine the high-resolution structures of important drug-target proteins, including membrane receptors and transporters, and thus structure-guided drug development has now become a realistic approach. In this chapter, we focus on two clinically important pathways involved in diseases associated with chronic inflammation, and summarise the recent results of our structural studies. In the first section, we focus on the signalling mediated by the lipid mediator lysophosphatidic acid, and discuss the structural findings for its producing enzyme and receptor. In the second section, we focus on the anaemia associated with inflammatory conditions, and discuss the structural insights into the iron exporter ferroportin, which plays a key role in the anaemia of chronic inflammation. These examples provide ideas for using structural information as the basis for pharmacological analyses.