Blockade of CD28 by a synthetical peptoid inhibits T-cell proliferation and attenuates graft-versus-host disease

Abstract

CD28 is one of the costimulatory molecules crucial for T-cell activation and thus has become an attractive target for therapeutic immunomodulation. Conventional strategies for blocking CD28 activity using monoclonal antibodies, Fab fragments, antagonistic peptide and fusion proteins, have apparent disadvantages such as inherent immunogenicity, unwanted Fc signaling, poor tissue penetration and bioinstability. Recent research has been directed toward the creation of non-natural, sequence-specific biomimetic oligomers with bioinspired structures that capture the amino-acid interface of the targeted proteins. One such family of molecules is the poly-N-substituted glycines or peptoids, which have close structural similarity to peptides but are essentially invulnerable to protease degradation. To screen for peptoids that specifically target CD28, we first designed and chemically synthesized 19 candidate peptoids based on molecular modeling and docking. Using the phage-displaying system that expresses the extracellular domain of the CD28 homodimer and contains the core B7-binding motif, a peptoid (No. 9) with a molecular formula of C 21 H 29 N 3 O 7 , was identified to display the highest binding activity to CD28. This peptoid not only inhibited the lymphocyte proliferation in vitro, but suppressed immunoresponses against alloantigens in vivo, and attenuated the graft-versus-host disease in a mouse bone-marrow transplantation model. These results suggested that peptoids targeting CD28 are effective agents for blocking the CD28-mediated costimulation and suitable for development of novel therapeutic approaches for diseases involving this pathway.

A CGenFF‐based force field for simulations of peptoids with both cis and trans peptide bonds

“…Decreased sampling of secondary minima helps explain reduced frequency of conformational transitions for larger peptoid side chains. The Ramachandran plots for the carboxy termini (ϕ 3 , ψ 3 ) show greater flexibility for all 3 trimers agreeing with Wus results showing that a carboxy terminus has some kind of stabilizing effect on peptoid helices …”

“…Peptoids are a type of synthetic, biomimetic foldamer (foldable polymer) composed of protein‐like, poly‐glycine backbones with side chains attached to their nitrogen atoms rather than their α‐carbons . Due to their resemblance to proteins, peptoids have applications as bioactive peptide mimics and targeted binders . At the same time, shifting the side chains from the α‐carbons to the backbone nitrogens changes peptoid folding behavior relative to proteins …”

Protection of Mice from Acute Graft-versus-Host Disease Requires CD28 Co-stimulation on Donor CD4+ Foxp3+ Regulatory T Cells

“…In published studies, induction of aGvHD was reduced to varying degrees, depending on the exact model employed, when CD28 −/− mice were used as T cell donors or when CD28 signaling was blocked ( 7 – 9 , 43 ). Accordingly, in the H-2 b into H-2 d model we used, CD28 deletion on Tconv did not abrogate aGvHD, but diminished inflammation during the first week after allo-HSCT (Figures 3 A–C).…”

Efficient sampling of high-dimensional free energy landscapes using adaptive reinforced dynamics

“…2a). Recently, peptoids receive growing interest due to their resemblance to peptides, with applications such as bioactive peptide mimics [14] and targeted binders [15,16]. Despite a great amount of efforts, including some recent ones [17][18][19][20], efficient sampling of peptoid configurations remains challenging and is far from being routine due to the high dimensionality and the large energy barriers in the space of torsion angles.…”