title: Engineering and screening the N-terminus of chemokines for drug discovery.
abstract: 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.
authors.affiliation: Laboratoire de Rétrovirologie, Centre de Recherche Public-Santé, 84, Val Fleuri, L-1526 Luxembourg, Luxembourg. andy.chevigne@crp-sante.lu
authors.forename: Andy
authors.initials: A
authors.lastname: Chevigné
authors.forename: Virginie
authors.initials: V
authors.lastname: Fievez
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Schmit
authors.forename: Sabrina
authors.initials: S
authors.lastname: Deroo
mesh_terms: D018925:Chemokines / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D005786:Gene Expression Regulation; D008958:Models, Molecular; D011487:Protein Conformation; D015202:Protein Engineering / Q000379:methods*
chemical_list: D018925:Chemokines