Structure-Based Design of Peptidic Inhibitors of the Interaction between CC Chemokine Ligand 5 (CCL5) and Human Neutrophil Peptides 1 (HNP1)

Kanin Wichapong*, Jean -Eric Alard, Almudena Ortega-Gomez, Christian Weber, Tilman M. Hackeng, Oliver Soehnlein, Gerry A. F. Nicolaes

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

23 Citations (Web of Science)


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 (K-D) 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.
Original languageEnglish
Pages (from-to)4289-4301
JournalJournal of Medicinal Chemistry
Issue number9
Publication statusPublished - 12 May 2016

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