Aberrant inflammation appears to be a pathogenic factor in autoimmune diseases and other noxious inflammatory conditions in which the inflammatory process is misapplied, exaggerated, recurrent or chronic. The protein molecules involved in pathogenic inflammation—disease-associated proteins (DAP)—which include chemokines, cytokines, and growth factors and their receptors, appear normal; their networks of interaction are at fault. Here we demonstrate a new approach to network regulation of inflammation based on peptide sequence motifs shared by the second extra-cellular loop (ECL2) of different chemokine receptors; previously known chemokine receptor binding sites have not involved the ECL2 loop. These motifs of 9 amino acids, which we detected by sequence alignment, manifest very low E-values compared with slightly modified sequence variations, indicating that they were not likely to have evolved by chance. To test whether this shared sequence network (SSN) might serve a regulatory function, we synthesized 9-amino acid SSN peptides from the ECL2 loops of three different chemokine receptors. We administered these peptides to rats during the induction of a model of autoimmune arthritis. Two of the peptides significantly downregulated the arthritis; one of the peptides synergized with non-specific anti-inflammatory treatment with dexamethasone. These findings suggest that the SSN peptide motif reported here is likely to have adaptive value in controlling inflammation. Moreover, detection of SSN motif peptides could provide a network-based approach to immune modulation.

The rationale for multi-target drugs has been strengthened both on theoretical and empirical grounds. Serious diseases that are intractable to treatment were found to have multiple pathogenic factors and examples of successful drugs were shown to affect multiple disease targets. The salient features of multiple-target drugs, low target affinity and rapid binding kinetics, have been responsible for their late discovery and slow development. We predicted that peptides from the ligand-binding domains of chemokine (CK) receptors could be used to modulate the activities of disease-related chemokines (CKs) for therapeutic effect. We developed innovative technologies to produce, screen and optimize low affinity, chemokine-binding peptides (CBPs) derived from chemokine receptors (CRs). The peptides were found to have therapeutic activity in animal models of disease, confirming our prediction and validating the related technologies.

Chemokines (CKs) are chemo-attractants that mobilize and activate leukocytes of the immune system. CKs and their receptors have become targets for drug discovery and development on the basis of correlations between their expression profiles and autoimmune diseases. Essential for both physiological immunity and pathological autoimmunity, these immune messengers and regulators have proven to be tantalizing drug targets. Drug inhibitors of disease-related CK receptors adversely affect physiological processes which are unrelated to the targeted disease. We argue that drugs which modulate, rather than negate CK activity, may be the answer to fortuitous and deleterious side effects. CKs, more than their receptors, lend themselves to therapeutic modulation that is disease specific.