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

作　　者：Na Li Faliang Zhu Fei Gao Qun Wang Xiaoyan Wang Haiyan Li Chunhong Ma Wensheng Sun Wenfang Xu Chaodong Wang Lining Zhang 

机构地区：[1]Institute of Immunology, Shandong University, Ji'nan, China [2]School of Pharmaceutical Sciences, Shandong University, Ji'nan, China [3]Department of Neurology, SanmingFirst Hospital, Fujian Medical University, Sanming, China [4]These authors contributed equally to this work.

出　　处：《Cellular & Molecular Immunology》2010年第2期133-142,共10页中国免疫学杂志（英文版）

摘　　要：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 C21H29N307, 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.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 C21H29N307, 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.

关 键 词：CD28 PEPTOID phage display 

分 类 号：Q343[生物学—遗传学] X591[环境科学与工程—环境工程]