The Cell Surface Receptor CD44: NMR‐Based Characterization of Putative Ligands. (4th May 2016)

• Record Type: Journal Article
• Authors: Baggio, Carlo; Barile, Elisa; Di Sorbo, Gianluigi; Kipps, Thomas J.; Pellecchia, Maurizio
• Is Part Of: ChemMedChem. Volume 11:Number 10(2016)
• Page Start: 1097
• Page End: 1106
• Publication Date: 2016-05-04
• Subjects: cell recognition -- drug discovery -- inhibitors -- peptides -- protein–protein interactions; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201600039
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: The cell surface receptor CD44 is a glycoprotein belonging to the hyaluronan‐binding proteins, termed hyaladherins. CD44 is expressed in a wide variety of isoforms in many cells and, in particular, is present on the surface of malignant cells where it is involved in the onset and progression of cancer. In a first attempt to identify novel CD44‐binding agents, we first characterized, with NMR spectroscopic techniques, several agents that were reported to bind to human CD44 (hCD44). To our surprise, however, none of these putative CD44‐binding agents, including a peptide that is in phase 2 clinical trials (A6 peptide) and a recently reported fragment hit, were found to interact significantly with recombinant hCD44(21–178). Nonetheless, we further report that a fragment‐screening campaign, with solution NMR spectroscopy as the detection method, identified a viable fragment hit that bound in a potentially functional pocket on the surface of CD44, opposite to the hyaluronic acid binding site. We hypothesize that this pocket could be indirectly associated with the cellular and in vivo activity of the A6 peptide, which would provide a novel framework for the possible development of therapeutically viable CD44 antagonists. Abstract : Keep it in a back pocket : With the aim of finding an inhibitor of human cell surface receptor hCD44, the binding properties of its putative ligands were first evaluated with solution NMR spectroscopy. Apart from its natural ligand HA8 and the antibody DF1485, none of the putative ligands bound significantly to recombinant hCD44(21–178). However, fragment screening identified and validated a fragment hit that bound to a possibly 'druggable' back pocket of hCD44(21–178) that may have functional implications.