(680d) Rational Design of a 'marker of Self' Peptide

Macrophages are the primary policing cells in your body and respond upon contact in a two-step process. In the first step, invariably, the macrophage is activated by contact to anything, even your own cells. However, in the second stage, and just before a macrophage engulfs its target, it checks for identification, that includes the 'marker of self' protein CD47, a widely expressed membrane protein. If CD47 is present, it causes the macrophage to disengage, making the activated phagocytosis process less efficient. Attachment of "self" CD47 on avidin-beads has shown a reduction in the rate of the phagocytosis by the macrophage.

The technical difficulty of expressing CD47's functional domain led us to search for a smaller peptide showing phagocytosis inhibition. In this direction we used molecular dynamics simulations and docking algorithms to understand the binding process and design a useful peptide. We used as a template the crystallographic structure of the complex of CD47 with the N-terminal ligand-binding domain of signal regulatory protein alpha (SIRP-α). We tested two different peptides, each of them represent two different strategies aiming to preserve the binding region from diverging from the crystal structure. We found that one of these strategies maintained the structure better than the other. Affinity experiments agreed with our predictions, and suggest the real possibility of more biocompatible materials with a small peptide.