Neutralizing endogenous chemokines with small molecules. Principles and potential therapeutic applications

Abstract

Regulation of cellular responses to external stimuli such as hormones, neurotransmitters, or cytokines is achieved through the control of all steps of the complex cascade starting with synthesis, going through maturation steps, release, distribution, degradation and/or uptake of the signalling molecule interacting with the target protein. One possible way of regulation, referred to as scavenging or neutralization of the ligand, has been increasingly studied, especially for small protein ligands. It shows innovative potential in chemical biology approaches as well as in disease treatment. Neutralization of protein ligands, as for example cytokines or chemokines can lead to the validation of signalling pathways under physiological or pathophysiological conditions, and in certain cases, to the development of therapeutic molecules now used in autoimmune diseases, chronic inflammation and cancer treatment. This review explores the field of ligand neutralization and tries to determine to what extent small chemical molecules could substitute for neutralizing antibodies in therapeutic approaches.

Fig. 1

Folding of chemokines: chemokine adopts a typical structure with 3 anti-parallel β-strands and one carboxy terminal helix. C–C denotes disulfide bridges.

Fig. 2

Examples of different possible routes that can be followed by chemokines/cytokines in the presence of neutralizing macromolecules. Route 1 leads to signalling in the target cell expressing the chemokine/cytokine receptor. Route 2 is used either endogenously or by pathogens. Binding of chemokines takes place without signalling. This event may either lead to degradation of the chemokine or to its transcytosis. Route 3 is used by pathogens that express soluble proteins capable of binding chemokines, generally with moderate affinity and selectivity, and prevents them from normal signalling to the immune system. In Route 4, the neutralizing molecule prevents chemokine binding to glycosaminoglycans. The resulting effect is a collapse of the chemotactic gradient that abolishes leukocyte attraction in the inflamed tissue.

Fig. 3

Superimposition of peptide backbones from CC, CXC and CX3C chemokine groups shows that they have a canonical three dimensional structure.

Fig. 4

Illustration of the different modes of action of neutralizing molecules. a) The small molecule competitively binds to the same site as the receptor. b) The small chemical molecule alters the quaternary structure of the protein ligand. c) The protein ligand undergoes structural changes that regulate its activity: the small molecule alters tertiary structure of the protein ligand.

Fig. 5

Proposed model for the interaction between CXCL12 and neutralizing chalcone molecule 4. Redrawn from Hachet-Haas et al. (2008).