title: Synthesis of diastereomerically pure Lys(Nε-lipoyl) building blocks and their use in Fmoc/tBu solid phase synthesis of lipoyl-containing peptides for diagnosis of primary biliary cirrhosis.
abstract: Primary Biliary Cirrhosis is an immune-mediated disease in which one of the epitopes recognized by antimitochondrial autoantibodies is a lipoylated fragment of the PDC-E2 protein. Accordingly, the synthesis of lipoylated peptides as diagnostic tools is a relevant target. Up to now, the proper tools for the introduction of lipoylation on building blocks to be used in Fmoc/tBu solid phase peptide synthesis (SPPS) are lacking, and the role of chirality in lipoylation remains poorly studied. In this paper, we present the synthesis of lipoylated lysine derivatives as pure diastereomeric building blocks suitable for Fmoc/tBu SPPS and their introduction in relevant peptide sequences to possibly serve as synthetic probes for the development of novel diagnostic tools for this disease. The optimization of the synthesis of lipoylated building blocks derived from racemic, (R)-, and (S)-α-lipoic acid is described. Synthesis of peptide probes incorporating lipoylation is described. An insight regarding the cleavage of lipoylated peptides is given, as well as a method to oxidize or reduce the 1,2-dithiolane ring of the lipoyl moiety directly on the peptide without any subsequent purification.
authors.affiliation: French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry & Biology - PeptLab; Laboratoire de Chimie Biologique EA4505, University of Cergy-Pontoise, 5 mail Gay-Lussac, Neuville-sur-Oise, 95000, Cergy-Pontoise, France; Department of Chemistry "Ugo Schiff", University of Florence, Via della Lastruccia 3/13, I-50019, Sesto Fiorentino, Italy.
authors.forename: Cédric
authors.initials: C
authors.lastname: Rentier
authors.forename: Giulia
authors.initials: G
authors.lastname: Pacini
authors.forename: Francesca
authors.initials: F
authors.lastname: Nuti
authors.forename: Elisa
authors.initials: E
authors.lastname: Peroni
authors.forename: Paolo
authors.initials: P
authors.lastname: Rovero
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Papini
mesh_terms: D051047:Dihydrolipoyllysine-Residue Acetyltransferase / Q000737:chemistry* / Q000276:immunology; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D006801:Humans; D054878:Lipoylation; D008105:Liver Cirrhosis, Biliary / Q000175:diagnosis; D008239:Lysine / Q000737:chemistry*; D015394:Molecular Structure; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000276:immunology; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000939:Epitopes; D010455:Peptides; D051047:Dihydrolipoyllysine-Residue Acetyltransferase; D008239:Lysine
keywords: building block; chemical reverse approach; lipoic acid; lipoyl-lysine; primary biliary cirrhosis; solid phase peptide synthesis