title: Tolerogenic modulation of the immune response by oligoglycerol- and polyglycerol-peptide conjugates.
abstract: Peptide-based therapy is a promising strategy for antigen-specific immunosuppression to treat or even heal autoimmune diseases with significantly reduced adverse effects compared to conventional therapies. However, there has been no major success due to the drawbacks of native peptides, i.e., limited bioavailability. Considering the importance and limitations of peptide-based therapies for treatment of autoimmune diseases, we designed and constructed oligoglycerol (OG)- and polyglycerol (PG)-based peptide conjugates. They were evaluated for their biological activity (in vitro and in vivo), bioavailability, and tolerogenic potential. Among the OG- and PG-peptide constructs, PG-peptide constructs exhibited an extended bioavailability compared to OG-peptide constructs and unconjugated peptide. Interestingly, size, structure, and linker chemistry played a critical role for the tolerogenic capacity of the constructs. The PG-peptide construct bound via an ester linkage was the most tolerogenic conjugate, while the PG-peptide construct bound via an amide induced stronger proliferation, but also higher TNF production and lower frequencies of Foxp3(+) regulatory T-cells. Therefore, we conclude that PG-peptide conjugates bound via an ester linkage are not only promising candidates for tolerogenic vaccination, but also open a new avenue toward the application of peptides for the treatment of autoimmune diseases.
authors.affiliation: †Organic and Macromolecular Chemistry, Department of Chemistry and Biochemistry, Free University Berlin, Takustrasse 3, 14195 Berlin, Germany.|‡Department of Chemistry, Hindu College, Sonepat-131001, Haryana, India.
authors.forename: Shilpi
authors.initials: S
authors.lastname: Gupta
authors.affiliation: §Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pfeil
authors.affiliation: †Organic and Macromolecular Chemistry, Department of Chemistry and Biochemistry, Free University Berlin, Takustrasse 3, 14195 Berlin, Germany.|∥Department of Chemistry, Deenbandhu Chhotu Ram University of Science and Technology, Murthal, Sonepat-131039, Haryana, India.
authors.forename: Sumit
authors.initials: S
authors.lastname: Kumar
authors.affiliation: §Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Poulsen
authors.affiliation: §Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Lauer
authors.affiliation: §Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
authors.affiliation: §Deutsches Rheuma-Forschungszentrum and Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: †Organic and Macromolecular Chemistry, Department of Chemistry and Biochemistry, Free University Berlin, Takustrasse 3, 14195 Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
mesh_terms: D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001682:Biological Availability; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry* / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects*; D007155:Immunologic Factors / Q000737:chemistry / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D010047:Ovalbumin / Q000737:chemistry* / Q000276:immunology; D010455:Peptides / Q000737:chemistry* / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013329:Structure-Activity Relationship; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007155:Immunologic Factors; D010455:Peptides; D011108:Polymers; D011948:Receptors, Antigen, T-Cell; D014409:Tumor Necrosis Factor-alpha; C043941:polyglycerol; D010047:Ovalbumin; D005990:Glycerol