title: Scaffold optimization in discontinuous epitope containing protein mimics of gp120 using smart libraries.
abstract: A diversity of protein surface discontinuous epitope mimics is now rapidly and efficiently accessible. Despite the important role of protein-protein interactions involving discontinuous epitopes in a wide range of diseases, mimicry of discontinuous epitopes using peptide-based molecules remains a major challenge. Using copper(I) catalyzed azide-alkyne cycloaddition (CuAAC), we have developed a general and efficient method for the synthesis of collections of discontinuous epitope mimics. Up to three different cyclic peptides, representing discontinuous epitopes in HIV-gp120, were conjugated to a selection of scaffold molecules. Variation of the scaffold molecule, optimization of the ring size of the cyclic peptides and screening of the resulting libraries for successful protein mimics led to an HIV gp120 mimic with an IC50 value of 1.7 μM. The approach described here provides rapid and highly reproducible access to clean, smart libraries of very complex bio-molecular constructs representing protein mimics for use as synthetic vaccines and beyond.
authors: Medicinal Chemistry & Chemical Biology, Utrecht Institute of Pharmaceutical Sciences, Faculty of Science, Utrecht, The Netherlands.
authors: Gwenn E
authors: GE
authors: Mulder
authors: H Linda C
authors: HL
authors: Quarles van Ufford
authors: Jeroen
authors: J
authors: van Ameijde
authors: Arwin J
authors: AJ
authors: Brouwer
authors: John A W
authors: JA
authors: Kruijtzer
authors: Rob M J
authors: RM
authors: Liskamp
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry; D000595:Amino Acid Sequence; D001386:Azides / Q000138:chemical synthesis / Q000737:chemistry; D002384:Catalysis; D003300:Copper / Q000737:chemistry; D061565:Cycloaddition Reaction; D000939:Epitopes / Q000737:chemistry*; D006678:HIV / Q000737:chemistry* / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000378:metabolism; D015658:HIV Infections / Q000821:virology*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019151:Peptide Library; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D060327:Solid-Phase Synthesis Techniques; D014614:Vaccines, Synthetic / Q000737:chemistry
chemical_list: D000480:Alkynes; D001386:Azides; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D019151:Peptide Library; D010456:Peptides, Cyclic; D014614:Vaccines, Synthetic; D003300:Copper