Abstract:
:Previous work from our laboratories has demonstrated that purified, recombinant human astrovirus coat protein (HAstV CP) binds C1q and mannose-binding lectin (MBL) inhibiting activation of the classical and lectin pathways of complement, respectively. Analysis of the 787 amino acid CP molecule revealed that residues 79-139 share limited sequence homology with human neutrophil defensin-1 (HNP-1), a molecule previously demonstrated to bind C1q and MBL, inhibiting activation of the classical and lectin pathways of complement, respectively. A 30 amino acid peptide derived from this region of the CP molecule competitively inhibited the binding of wild-type CP to C1q. The parent peptide and various derivatives were subsequently assayed for C1q binding, inhibition of C1 and C4 activation as well as suppression of complement activation in hemolytic assays. The parent peptide and several derivatives inhibited complement activation in these functional assays to varying degrees. One peptide derivative in particular (E23A) displayed superior inhibition of complement activation in multiple assays of classical complement pathway activation. Further analysis revealed homology to a plant defensin allowing development of a proposed structural model for E23A. Based upon these findings, we hypothesize that further rationale optimization of E23A may result in a promising therapeutic inhibitor for the treatment of inflammatory and autoimmune diseases in which dysregulated activation of the classical and lectin pathways of complement contribute to pathogenesis.
journal_name
Mol Immunoljournal_title
Molecular immunologyauthors
Gronemus JQ,Hair PS,Crawford KB,Nyalwidhe JO,Cunnion KM,Krishna NKdoi
10.1016/j.molimm.2010.07.012subject
Has Abstractpub_date
2010-11-01 00:00:00pages
305-13issue
1-3eissn
0161-5890issn
1872-9142pii
S0161-5890(10)00526-2journal_volume
48pub_type
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