1. Structure-Based Design of Peptidic Inhibitors of the Interaction between CC Chemokine Ligand 5 (CCL5) and Human Neutrophil Peptides 1 (HNP1)
- Author
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Christian Weber, Tilman M. Hackeng, Almudena Ortega-Gomez, Kanin Wichapong, Jean Eric Alard, Oliver Soehnlein, Gerry A. F. Nicolaes, Pathology, Biochemie, RS: CARIM - R3.07 - Structure-function analysis of the chemokine interactome for therapeutic targeting and imaging in atherosclerosis, and RS: CARIM - R1.01 - Blood proteins & engineering
- Subjects
0301 basic medicine ,Chemokine ,alpha-Defensins ,Human neutrophil ,Protein Conformation ,In silico ,Druggability ,Peptide ,01 natural sciences ,CCL5 ,Monocytes ,03 medical and health sciences ,In vivo ,Drug Discovery ,Cell Adhesion ,Humans ,Chemokine CCL5 ,chemistry.chemical_classification ,biology ,In vitro ,0104 chemical sciences ,010404 medicinal & biomolecular chemistry ,030104 developmental biology ,Biochemistry ,chemistry ,Drug Design ,biology.protein ,Molecular Medicine ,Thermodynamics ,Peptides ,Dimerization - 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.
- Published
- 2016