Lipidation of W-peptide to Develop Anti-Inflammatory Therapeutics.
Rodenstein, Marissa.
2015
- The W-peptide (WKYMVM-NH2/WKYMVmNH2) is a hexapeptide agonist of the formyl peptide receptor (FPR) family of G-protein coupled receptors (GPCRs) that act as checkpoints in host defense and can thus be exploited for anti-inflammatory drugs. Discovered through a hexapeptide screening, WKYMVM-NH2 was determined to be a chemoattractant, acting to attract neutrophils to sites of inflammation and infection. ... read moreThrough later experimentation with D-amino acids showed that a C-terminal D-Met (WKYMVm-NH2) caused a 120-fold increase in activity as compared to WKYMVM-NH2, with the EC50 value decreasing from 60nM to 0.5nM. WKYMVm-NH2 was shown to activate the FPR family in Class F of GCPRs, including FPR1 and FPR2. Both the L and D versions of the W-peptide have been shown to activate FPR2, whereas the D version also stimulates FPR1. In vivo the D version has produced anti-inflammatory effects that have proved therapeutic for ailments in murine models. To increase the potency and therapeutic possibility, the W-peptides were synthesized with lipid anchors, as a small membrane-anchored ligand (SMAL), after use of a Membrane Tethered Ligand (MTL) Technology determined the N-terminal membrane anchoring to be a viable strategy. Moreover, by increasing the potency of the L version of the W-peptide, a more specific, targeted therapeutic could be produced for FPR2, which has been indicated to have cardioprotective and anti-sepsis effects. The addition of the membrane anchoring by lipid tail is hypothesized to increase signal transduction due to the increased local concentration of the ligand, which is restricted to the two dimensional surface of the membrane. The lipid tail itself will also allow interactions with blood serum albumin that should increase the bioavailability. Submitted in partial fulfillment of the grant requirement of the Tufts Summer Scholars Program.read less
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