Engineering and screening the N-terminus of chemokines for drug discovery

Chemokines are small chemoattractive proteins involved in many important physiological and pathological processes such as leukocyte mobilisation, inflammation, cancer and HIV-1 infection. The N-terminus of chemokines was shown to be crucial for interaction and activation with their cognate receptors. Therefore, multiple strategies including elongation, truncation, mutagenesis or chemical modifications of chemokine N-terminus were developed to identify analogues with modified selectivity displaying antagonist or enhanced agonist activities. Library approaches allowed fast screening of a large number of such chemokine variants and led to the identification of promising therapeutic candidates. Additional studies were able to reduce the chemokine to the size of a peptide while retaining its receptor affinity and selectivity. In analogy to full length chemokines, peptides derived from the chemokine N-terminal sequence were improved by mutagenesis, elongation and truncation approaches to develop potential therapeutic molecules used in various clinical trials. Altogether these studies demonstrated the pharmacophore potential of the chemokine N-terminus and its vast modulation properties to develop analogues with great therapeutic value for a large set of pathologies. (C) 2011 Elsevier Inc. All rights reserved.