title: Structure-Based Design of Peptidic Inhibitors of the Interaction between CC Chemokine Ligand 5 (CCL5) and Human Neutrophil Peptides 1 (HNP1).
abstract: Protein-protein interactions (PPIs) are receiving increasing interest, much sparked by the realization that they represent druggable targets. Recently, we successfully developed a peptidic inhibitor, RRYGTSKYQ ("SKY" peptide), that shows high potential in vitro and in vivo to interrupt a PPI between the platelet-borne chemokine CCL5 and the neutrophil-derived granule protein HNP1. This PPI plays a vital role in monocyte adhesion, representing a key mechanism in acute and chronic inflammatory diseases. Here, we present extensive and detailed computational methods applied to develop the SKY peptide. We combined experimentally determined binding affinities (KD) of several orthologs of CCL5 with HNP1 with in silico studies to identify the most likely heterodimeric CCL5-HNP1 complex which was subsequently used as a starting structure to rationally design peptidic inhibitors. Our method represents a fast and simple approach that can be widely applied to determine other protein-protein complexes and moreover to design inhibitors or stabilizers of protein-protein interaction.
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors.forename: Kanin
authors.initials: K
authors.lastname: Wichapong
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich , 80336 Munich, Germany.
authors.forename: Jean-Eric
authors.initials: JE
authors.lastname: Alard
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich , 80336 Munich, Germany.
authors.forename: Almudena
authors.initials: A
authors.lastname: Ortega-Gomez
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , 6200 MD Maastricht, The Netherlands.|Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich , 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilians University Munich , 80336 Munich, Germany.|German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, 80336 Munich, Germany.|Department of Pathology, Academic Medical Center (AMC), University of Amsterdam , 1105 AZ Amsterdam, The Netherlands.
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.affiliation: Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University , 6200 MD Maastricht, The Netherlands.
authors.forename: Gerry A F
authors.initials: GA
authors.lastname: Nicolaes
mesh_terms: D002448:Cell Adhesion; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D019281:Dimerization; D015195:Drug Design; D006801:Humans; D009000:Monocytes / Q000166:cytology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013816:Thermodynamics; D023084:alpha-Defensins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D010455:Peptides; D023084:alpha-Defensins; C406413:human neutrophil peptide 1