title: Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2:CD58 Protein-Protein Interaction.
abstract: The interaction between the cell-cell adhesion proteins CD2 and CD58 plays a crucial role in lymphocyte recruitment to inflammatory sites, and inhibitors of this interaction have potential as immunomodulatory drugs in autoimmune diseases. Peptides from the CD2 adhesion domain were designed to inhibit CD2:CD58 interactions. To improve the stability of the peptides, β-sheet epitopes from the CD2 region implicated in CD58 recognition were grafted into the cyclic peptide frameworks of sunflower trypsin inhibitor and rhesus theta defensin. The designed multicyclic peptides were evaluated for their ability to modulate cell-cell interactions in three different cell adhesion assays, with one candidate, SFTI-a, showing potent activity in the nanomolar range (IC50: 51 nM). This peptide also suppresses the immune responses in T cells obtained from mice that exhibit the autoimmune disease rheumatoid arthritis. SFTI-a was resistant to thermal denaturation, as judged by circular dichroism spectroscopy and mass spectrometry, and had a half-life of ∼24 h in human serum. Binding of this peptide to CD58 was predicted by molecular docking studies and experimentally confirmed by surface plasmon resonance experiments. Our results suggest that cyclic peptides from natural sources are promising scaffolds for modulating protein-protein interactions that are typically difficult to target with small-molecule compounds.
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe , Monroe, Louisiana 71201, United States.
authors.forename: Rushikesh
authors.initials: R
authors.lastname: Sable
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience , Brisbane, Queensland 4072, Australia.
authors.forename: Thomas
authors.initials: T
authors.lastname: Durek
authors.affiliation: Department of Immunology, Mayo Clinic , Rochester, Minnesota 55905, United States.
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
authors.affiliation: The University of Queensland, Institute for Molecular Bioscience , Brisbane, Queensland 4072, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Craik
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe , Monroe, Louisiana 71201, United States.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Pallerla
authors.affiliation: LSU-Ag Center, Louisiana State University , Baton Rouge, Louisiana 70803, United States.
authors.forename: Ted
authors.initials: T
authors.lastname: Gauthier
authors.affiliation: Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe , Monroe, Louisiana 71201, United States.
authors.forename: Seetharama
authors.initials: S
authors.lastname: Jois
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D018801:CD2 Antigens / Q000378:metabolism*; D018968:CD58 Antigens / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002942:Circular Dichroism; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D020349:Surface Plasmon Resonance
chemical_list: D000276:Adjuvants, Immunologic; D018801:CD2 Antigens; D018968:CD58 Antigens; D010456:Peptides, Cyclic