Chemokine receptor antagonism as an approach to anti-inflammatory therapy: ‘just right’ or plain wrong?

Abstract

Inflammation plays a pivotal role in exacerbating a wide array of human diseases. The chemokines are a group of proteins that control the movement and activation of the immune cells involved in all aspects of the inflammatory response. Recently, their cognate receptors have attracted considerable interest as therapeutic targets, in part because they are G-protein-coupled receptors, which have been antagonized successfully before by the pharmaceutical industry. Indeed, several companies have now reported the development of selective small-molecule chemokine receptor antagonists, and some of these compounds have even entered human Phase I clinical trials. Preclinical studies of the responsiveness of murine models of inflammation to either pharmacologic or genetic intervention have suggested that antagonism of some chemokine receptors may well prove to be a safe and efficacious approach to anti-inflammatory therapy.

Introduction

The inflammatory response has traditionally been considered the driving force primarily for diseases that seem immediately connected to the immune system: allo/xenograft rejection (chronic and acute), hypersensitivity states (asthma, allergic rhinitis) and autoimmune disorders (rheumatoid arthritis, multiple sclerosis). Recently, our understanding of pathophysiology has expanded to reveal that an inflammatory response plays a key role in other diseases, such as atherosclerosis and Alzheimer's disease, and also causes excessive damage in an otherwise appropriate response to foreign pathogens (e.g. the response to tuberculosis). Thus, it is clear that there is a pressing medical need for therapeutic agents that either prevent or control inflammation.

Historically, our inability to deal directly with the constellation of antigenic immune ‘triggers’ has led us to try to dampen the inflammatory response itself. Most anti-inflammatory drugs have targeted mechanisms that were too fundamental or too ancillary, thereby rendering the drugs either broadly immunosuppressive (e.g. steroids, cyclosporine) or capable of doing little other than to manage disease symptoms (antihistamines, COX-2 inhibitors). The search for Goldilocks’ drug — the one that balances efficacy and selectivity and is ‘just right’ — has gone unrewarded thus far.

The chemokines (chemotactic cytokines) are a group of small (8–14 kDa) proteins that are firmly entangled in the immunological web of heterogeneity, and chemokine research has provided important advances in our understanding of the biochemical mechanisms of human immunity [1]. Given that individual chemokines play a role in both cell movement and cell activation (Fig. 1), it might be expected that chemokine antagonism would be efficacious. Moreover, because chemokines and their receptors are frequently localized to specific cell types, immunological functions, and even anatomical/physiological compartments, chemokine antagonism also holds out the promise of selective immune regulation. This review surveys the recent biological and chemical developments relevant to antagonizing chemokine networks as a modern approach to anti-inflammatory therapy. In the interest of space, the potential roles of chemokine receptors as targets for the treatment of HIV infection [2•] or cancer 3•., 4. are not considered here.