Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2: CD58 Protein-Protein Interaction

Rushikesh Sable, Thomas Durek, Veena D Taneja, David J. Craik, Sandeep Pallerla, Ted Gauthier, Seetharama Jois

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 7sim;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.

Original languageEnglish (US)
Pages (from-to)2366-2374
Number of pages9
JournalACS Chemical Biology
Volume11
Issue number8
DOIs
StatePublished - Aug 19 2016

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Cyclic Peptides
Peptides
Cell adhesion
Proteins
Cell Adhesion
Cell Communication
Autoimmune Diseases
Circular dichroism spectroscopy
Denaturation
Trypsin Inhibitors
T-cells
Lymphocytes
Surface Plasmon Resonance
Helianthus
Surface plasmon resonance
Circular Dichroism
Scaffolds
Inhibitory Concentration 50
Mass spectrometry
Half-Life

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Cite this

Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2 : CD58 Protein-Protein Interaction. / Sable, Rushikesh; Durek, Thomas; Taneja, Veena D; Craik, David J.; Pallerla, Sandeep; Gauthier, Ted; Jois, Seetharama.

In: ACS Chemical Biology, Vol. 11, No. 8, 19.08.2016, p. 2366-2374.

Research output: Contribution to journalArticle

Sable, Rushikesh ; Durek, Thomas ; Taneja, Veena D ; Craik, David J. ; Pallerla, Sandeep ; Gauthier, Ted ; Jois, Seetharama. / Constrained Cyclic Peptides as Immunomodulatory Inhibitors of the CD2 : CD58 Protein-Protein Interaction. In: ACS Chemical Biology. 2016 ; Vol. 11, No. 8. pp. 2366-2374.
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