Probing Functional Heteromeric Chemokine Protein–Protein Interactions through Conformation-Assisted Oxime Ligation

Stijn M. Agten, Rory R. Koenen, Hans Ippel, Veit Eckardt, Philipp von Hundelshausen, Kevin H. Mayo, Christian Weber, Tilman M. Hackeng

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES-PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function.

Original languageEnglish (US)
Pages (from-to)14963-14966
Number of pages4
JournalAngewandte Chemie - International Edition
Volume55
Issue number48
DOIs
StatePublished - 2016

Keywords

  • atherosclerosis
  • chemokines
  • oximes
  • protein–protein interactions
  • solid-phase synthesis

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