title: Generating Chemokine Analogs with Enhanced Pharmacological Properties Using Phage Display.
abstract: Phage display technology, which allows extremely rare ligands to be selected from libraries of variants according to user-defined selection criteria, has made a huge impact on the life sciences. In this chapter, we describe phage display methods for the discovery of chemokine analogs with enhanced pharmacological properties. We discuss strategies for chemokine library design and provide a recommended technique for library construction. We also describe cell-based library selection approaches that we have used to discover chemokine analogs, not only receptor antagonists but also variants with unusual effects on receptor signaling and trafficking. By providing a survey of the different phage chemokine projects that we have undertaken, we comment on the parameters most likely to affect success. Finally, we discuss how phage display-derived chemokine analogs with altered pharmacological activity represent valuable tools to better understand chemokine biology, and why certain among them have the potential to be developed as new medicines.
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm UMRS1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Dorgham
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Cerini
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Hubert
authors.initials: H
authors.lastname: Gaertner
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Astrid
authors.initials: A
authors.lastname: Melotti
authors.affiliation: Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Irène
authors.initials: I
authors.lastname: Rossitto-Borlat
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, Inserm UMRS1135, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France; Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: guy.gorochov@upmc.fr.
authors.forename: Guy
authors.initials: G
authors.lastname: Gorochov
authors.affiliation: AP-HP, Groupement Hospitalier Pitié-Salpêtrière, Département d'Immunologie, Paris, France. Electronic address: oliver.hartley@unige.ch.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hartley
mesh_terms: D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D018925:Chemokines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008967:Molecular Biology / Q000379:methods; D019151:Peptide Library; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000737:chemistry / Q000378:metabolism
chemical_list: C584933:CCR5 protein, human; D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D018925:Chemokines; D019151:Peptide Library; D019713:Receptors, CCR5; D019707:Receptors, Chemokine
keywords: CCR5; CX3CR1; Chemokine; Phage display; Pharmacology