title: Molecular construction of HIV-gp120 discontinuous epitope mimics by assembly of cyclic peptides on an orthogonal alkyne functionalized TAC-scaffold.
abstract: Mimics of discontinuous epitopes of for example bacterial or viral proteins may have considerable potential for the development of synthetic vaccines, especially if conserved epitopes can be mimicked. However, due to the structural complexity and size of discontinuous epitopes molecular construction of these mimics remains challeging. We present here a convergent route for the assembly of discontinuous epitope mimics by successive azide alkyne cycloaddition on an orthogonal alkyne functionalized scaffold. Here the synthesis of mimics of the HIV gp120 discontinuous epitope that interacts with the CD4 receptor is described. The resulting protein mimics are capable of inhibition of the gp120-CD4 interaction. The route is convergent, robust and should be applicable to other discontinuous epitopes.
authors.affiliation: Division of Medicinal Chemistry & Chemical Biology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, PO Box 80082, 3508 TB Utrecht, The Netherlands. r.m.j.liskamp@uu.nl.
authors.forename: P R
authors.initials: PR
authors.lastname: Werkhoven
authors.forename: M
authors.initials: M
authors.lastname: Elwakiel
authors.forename: T J
authors.initials: TJ
authors.lastname: Meuleman
authors.forename: H C
authors.initials: HC
authors.lastname: Quarles van Ufford
authors.forename: J A W
authors.initials: JAW
authors.lastname: Kruijtzer
authors.forename: R M J
authors.initials: RMJ
authors.lastname: Liskamp
mesh_terms: D000480:Alkynes / Q000737:chemistry*; D001386:Azides / Q000737:chemistry; D015704:CD4 Antigens / Q000378:metabolism; D061565:Cycloaddition Reaction; D000939:Epitopes / Q000737:chemistry* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D055767:Immobilized Proteins / Q000138:chemical synthesis / Q000737:chemistry* / Q000276:immunology; D008958:Models, Molecular; D015394:Molecular Structure; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000276:immunology; D013329:Structure-Activity Relationship; D014614:Vaccines, Synthetic / Q000737:chemistry* / Q000276:immunology
chemical_list: D000480:Alkynes; D001386:Azides; D015704:CD4 Antigens; D000939:Epitopes; D015699:HIV Envelope Protein gp120; D055767:Immobilized Proteins; D010456:Peptides, Cyclic; D014614:Vaccines, Synthetic