Anchor Therapeutics today announced the publication of new research in the Proceedings of the National Academy of Sciences USA. The paper describes the identification and characterization of a pepducin-based allosteric agonist that targets CXCR4, a chemokine G protein-coupled receptor (GPCR) found on hematopoietic stem cells and other bone marrow-derived cells. Pepducins are composed of a peptide coupled to a lipid tether - the amino acid sequence of the pepducin is derived from one of the intracellular loops of a target GPCR. This publication represents the first account of an in vivo active pepducin agonist and demonstrates the promise for pepducin technology as a novel approach to target therapeutically important GPCRs.
“Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells”
This study, Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells, describes a unique approach to the development of GPCR-targeted therapeutics using Anchor's proprietary pepducin technology. A small pepducin library was created using reverse engineering based on the natural sequences of the intracellular loops of CXCR4. In vitro screening resulted in the identification of several pepducins with agonist activity. The paper details one of the most potent of these agonist compounds (ATI-2341), which induced receptor- and G protein-dependent signaling in CXCR4-expressing cells and was shown to be active in vivo. When administered locally, the compound induced dose-dependent recruitment of neutrophils and, when administered systemically, ATI-2341 mobilized bone marrow-derived neutrophils and hematopoietic progenitor cells into circulation. ATI-2341 therefore appears to have multiple beneficial properties that may represent a powerful new modality for a range of therapeutic applications including stem cell therapy and repair of tissue injury.
"We believe this work represents a breakthrough in designing synthetic allosteric agonists for chemokine GPCRs," commented Thomas Sakmar, M.D., the Richard M. and Isabel P. Furlaud Professor of Molecular Biology and Biochemistry at the Rockefeller University and an author on the paper. "Our findings suggest that the allosteric pepducin agonist exhibits many of the same activities as the natural orthosteric ligand. This paper describes and supports the use of pepducins as a novel approach to target GPCRs and achieve results, such as the allosteric agonist modulation of CXCR4, that were previously not possible."
Stephen Hunt, Ph.D., Chief Scientific Officer and Senior Vice President of Discovery Research at Anchor said, "This paper highlights the ability of our pepducin technology to enable rapid discovery of GPCR agonists and antagonists based on GPCR sequence information. The ability of this compound to recruit CXCR4-expressing cells provides a unique pharmacological approach to stem and progenitor cell recruitment and lays the foundation for the Company's development of these molecules for regenerative medicine."
Source: Anchor Therapeutics