title: Synthesis and optimization of peptidomimetics as HIV entry inhibitors against the receptor protein CD4 using STD NMR and ligand docking.
abstract: We recently described the design and synthesis of a novel CD4 binding peptidomimetic as a potential HIV entry inhibitor with a KD value of approximately 35 microM and a high proteolytic stability [A. T. Neffe and B. Meyer, Angew. Chem., Int. Ed., 2004, 43, 2937-2940]. Based on saturation transfer difference (STD) NMR analyses and docking studies of peptidomimetics we now report the rational design, synthesis, and binding properties of 11 compounds with improved binding affinity. Surface plasmon resonance (SPR) resulted in a KD = 10 microM for the best peptidomimetic XI, whose binding affinity is confirmed by STD NMR (KD = 9 microM). The STD NMR determined binding epitope of the ligand indicates a very similar binding mode as that of the lead structure. The binding studies provide structure activity relationships and demonstrate the utility of this approach.
authors.affiliation: Institute for Organic Chemistry, University of Hamburg, Martin Luther King Platz 6, 20146, Hamburg. axel@neffe.org
authors.forename: Axel T
authors.initials: AT
authors.lastname: Neffe
authors.forename: Matthias
authors.initials: M
authors.lastname: Bilang
authors.forename: Bernd
authors.initials: B
authors.lastname: Meyer
mesh_terms: D001665:Binding Sites; D015704:CD4 Antigens / Q000737:chemistry / Q000187:drug effects*; D030562:Databases, Protein; D005998:Glycine; D006678:HIV / Q000187:drug effects / Q000502:physiology*; D008024:Ligands; D008239:Lysine; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology*; D011392:Proline; D013912:Threonine; D014633:Valine
chemical_list: D015704:CD4 Antigens; D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D013912:Threonine; D011392:Proline; D014633:Valine; D008239:Lysine; D005998:Glycine