PI: Michael Gelb
Location: UW Chemistry
Cyclic peptide inhibitors of secreted phospholipases A2 to dissect the roles of these enzymes in inflammatory diseases
Secreted phospholipases A2 (sPLA2s) are a group of 10 enzymes in humans and mice that function in inflammatory processes. The function of some of the family members are well known, but others are under investigation. We have X-ray crystal structures of several mammalian sPLA2s with and without bound inhibitors. The WRF-IPD project will be to use Rosetta computational design methods to design tight-binding cyclic peptide inhibitors of mammalian sPLA2s. The full set of human and mouse SPLA2s are available for inhibitor testing. The WRF-IPD Fellow will carryout computational design of cyclic peptides and also prepare cyclic peptides by modern solid-phase synthesis techniques. The cyclic peptides will be tested for sPLA2 inhibition potency and specificity in vitro as well as with cell lines that either overexpress a particular sPLA2 or that express an endogenous sPLA2 for which the biological function is to be probed by inhibition. Many actions of sPLA2s on cells are extracellular, thus it is not required that the cyclic peptide enter cells. We are particularly interested in groups IIA and X sPLA2s because of recent data obtained in mice inflammatory models that the former plays a pro-inflammatory role in rheumatoid arthritis, while the latter plays a pro-inflammatory role in asthma.