Discovery of Highly Potent and Selective CXCR4 Inhibitors Using Protein Epitope Mimetics (PEM) Technology

Authors

  • Alexander Lederer
  • John A. Robinson
  • Kerstin Moehle
  • Thomas Klimkait
  • François Hamy
  • Vincent Brondani
  • Sergio Lociuro
  • Jean-Pierre Obrecht
  • Jan Willem Vrijbloed
  • Christian Ludin
  • Frank O. Gombert
  • Federico Brianza
  • Jürg Zumbrunn
  • Reshmi Mukherjee
  • Barbara Romagnoli
  • Heiko Henze
  • Steven J. DeMarco
  • Daniel Obrecht

DOI:

https://doi.org/10.2533/chimia.2007.147

Keywords:

Cxcr4 inhibitor, Drug design, Peptide, Protein epitope mimetics, Stem cell mobilization

Abstract

Novel, highly potent CXCR4 inhibitors with good pharmacokinetic properties were obtained by applying PEM technology starting from the naturally occurring ?-hairpin peptide polyphemusin II. The design involved incorporation of key residues from polyphemusin II into a macrocyclic template-bound ?-hairpin mimetic. Using a parallel synthesis approach, the potency and ADME properties of the mimetics were optimized, resulting in CXCR4 inhibitors such as POL2438 and POL3026. Their activities were confirmed in a series of in vitro HIV-1 infection assays. Besides high selectivity for CXCR4, POL3026 had excellent plasma stability and favorable pharmacokinetic properties in dogs. In a murine model POL3026 was highly efficacious in hematopoietic stem cell mobilization. Hence, PEM-based CXCR4 inhibitors have the potential to become therapeutic agents for the treatment of HIV infections (as entry inhibitor), cancer (e.g. for inhibition of metastasis), stem cell transplant and inflammation.

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Published

2007-04-25