title: The Cell Surface Receptor CD44: NMR-Based Characterization of Putative Ligands.
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.
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA, 92521, USA.|Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Baggio
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA, 92521, USA.|Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.affiliation: Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA.
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Di Sorbo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California Riverside, 900 University Avenue, Riverside, CA, 92521, USA. maurizio.pellecchia@ucr.edu.|Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, CA, 92037, USA. maurizio.pellecchia@ucr.edu.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002151:Calorimetry; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008024:Ligands; D010455:Peptides; D011994:Recombinant Proteins
keywords: cell recognition; drug discovery; inhibitors; peptides; protein-protein interactions