Potent inhibition of the classical pathway of complement by a novel C1q-binding peptide derived from the human astrovirus coat protein.
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.
Gronemus
Jenny Q
JQ
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, 700 West Olney Road, Norfolk, VA 23507-1696, USA.
Hair
Pamela S
PS
Crawford
Katrina B
KB
Nyalwidhe
Julius O
JO
Cunnion
Kenji M
KM
Krishna
Neel K
NK
D000595:Amino Acid Sequence; D036022:Capsid Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism*; D003167:Complement Activation / Q000276:immunology; D015922:Complement C1q / Q000378:metabolism*; D003171:Complement Pathway, Classical / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D001257:Mamastrovirus / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D036022:Capsid Proteins; D010455:Peptides; D015922:Complement C1q