Journal
MATRIX BIOLOGY
Volume 31, Issue 1, Pages 66-77Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.matbio.2011.10.003
Keywords
Mac-1; CD11b-I-domain; Phage display; Peptide; Mimotope; Antagonist; Adhesion
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Funding
- Swiss National Fund for Scientific Research
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The leukocyte beta 2 integrin Mac-1 (CD11b/CD18) plays a pivotal role in inflammation and host defense. To develop peptide antagonists selectively inhibiting the function of Mac-1, we used a random constrained 6-mer (cys-6aa-cys) peptide library to map the structural features of CD11b, by determining the epitope of neutralizing monoclonal antibody mAb 44a (anti-CD11b). We have used a stringent phage display strategy, which resulted in the identification of one disulfide C-RLKEKH-C constrained peptide by direct biopanning of library on decreasing amounts of purified mAb 44a. The selected peptide mimics a discontinuous epitope, a peculiar shape on the CD11b-I-domain surface. Competitive ELISA experiments with different Mac-1 ligands showed that C-RLKEKH-C is able to bind to fibrinogen, iC3b, and C1q. Furthermore, the monomeric circular peptide C-RLKEKH-C, was effective in blocking the interaction between I-125-fibrinogen and Mac-1 (IC50 = 335 +/- 0.1 x 10(-6) M), and inhibited the adhesion of human neutrophils to fibrinogen and iC3b. These data provide information about the relative location of amino acids on the I-domain surface using mAb 44a imprint of the CD11b protein. The derived mimotope may help in the design of future anti-inflammatory therapeutic agents that can act as specific therapeutic agents targeting PMNs mediated inflammation. (C) 2011 Elsevier B.V. All rights reserved.
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