NMR in the analysis of functional chemokine interactions and drug discovery

Abstract

The involvement of chemokines and chemokine receptors in a great variety of pathological indications underscores their utility as therapeutic targets. In general, chemokine-mediated migration and signaling requires three distinct interactions: self-association, glycosaminoglycan (GAG) binding, and activation of G protein-coupled receptors (GPCRs). Solution-state nuclear magnetic resonance (NMR) spectroscopy has long been used to determine the apo structure of chemokines and monitor complex formation; however, it has never contributed directly to drug discovery efforts that are traditionally focused on the previously inaccessible chemokine receptors. Our lab recently demonstrated that NMR structures can be successfully utilized to direct drug discovery against chemokines. The ease of collecting chemokine structural data coupled with the increased efficiency of structure-based drug discovery campaigns makes chemokine-directed therapies particularly attractive. In addition, recent advances in sample preparation, spectrometer hardware, and pulse program development are allowing researchers to examine interactions with previously inaccessible partners - including full-length chemokine receptors. These developments will facilitate exploration of novel ways to modulate chemokine activity using structure-guided drug discovery.