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Random phage-epitope library based identification of a peptide antagonist of Mac-1 β2 integrin ligand binding.

Abstract : The leukocyte β2 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 (125)I-fibrinogen and Mac-1 (IC(50)=3.35±0.1×10(-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.
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https://hal-riip.archives-ouvertes.fr/pasteur-00658321
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Submitted on : Tuesday, January 10, 2012 - 11:42:59 AM
Last modification on : Monday, October 8, 2018 - 5:44:07 PM

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Mehdi Houimel, Luca Mazzucchelli. Random phage-epitope library based identification of a peptide antagonist of Mac-1 β2 integrin ligand binding.. Matrix Biology, Elsevier, 2011, epub ahead of print. ⟨10.1016/j.matbio.2011.10.003⟩. ⟨pasteur-00658321⟩

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