De Novo Peptide Design
with C3a Receptor Agonist and
Antagonist Activities: Theoretical Predictions and Experimental Validation
- Publication date
- Publisher
Abstract
Targeting the complement component 3a receptor (C3aR)
with selective
agonists or antagonists is believed to be a viable therapeutic option
for several diseases such as stroke, heart attack, reperfusion injuries,
and rheumatoid arthritis. We designed a number of agonists, partial
agonists, and antagonists of C3aR using our two-stage de novo protein
design framework. Of the peptides tested using a degranulation assay
in C3aR-transfected rat basophilic leukemia cells, two were prominent
agonists (EC<sub>50</sub> values of 25.3 and 66.2 nM) and two others
were partial agonists (IC<sub>50</sub> values of 15.4 and 26.1 nM).
Further testing of these lead compounds in a calcium flux assay in
U937 cells yielded similar results although with reduced potencies
compared to transfected cells. The partial agonists also displayed
full antagonist activity when tested in a C3aR inhibition assay. In
addition, the electrostatic potential profile was shown to potentially
discriminate between full agonists and partial agonists