Characterization of ICAM-1 biophore to design cytoadherence blocking peptides

Peptides from natural sources are good starting material to design bioactive agents with desired therapeutic property. IB peptide derived from the ICAM-1 has been studied extensively as an agent to disrupt the non-specific binding of lymphocyte to the endothelial cells. ICAM-1: IB molecular model reveals that IB peptide binds in an extended conformation to the ICAM-1, masking LFA-1 and partially covering PfEMP-1 binding site. Considering the regioselective requirement of ICAM-1: PfEMP1 binding site, IB peptide charge and 3-D conformation are optimized through generation of combinatorial peptide library containing single, double, triple, tetra and quadra amino acid substitutions of IB peptide. Further, truncation of IB peptide followed by molecular modeling studies gave us the biophoric environment of the IB peptide required for its activity. Molecular modeling of these peptides into the binding site indicates that these complexes are fitting well into the site and making extensive interactions with the residues crucial for PfEMP-1 binding. Molecular dynamics simulations were performed for 10ns each under four different temperatures to estimate comparative stability of ICAM1: IB peptide complexes. The designed peptide ICAM1: IBT213 has comparable stability at ambient temperature, while ICAM1: IBT1 shows a greater degree of robustness at higher temperatures. Overall, the study has given useful insights into IB peptide binding site on ICAM1 and its potential in designing novel peptides to disrupt the cytoadherence complex involving ICAM1: PfEMP1.