Pharmacological characterization of soluble and membrane anchored agonists of formyl peptide receptors.
peptide receptors (FPRs) are a family of G protein-coupled receptors found on monocytes,
polymorphonuclear leukocytes, dendritic cells, macrophages, and in other tissues. FPRs
have been shown to have a putative role in both the acute inflammatory response and
chronic inflammation. WKYMVM and its D-enantiomer WKYKVm (W-peptides) are a pair of
synthetic hexapeptides that are ... read morepromiscuous agonists of FPRs. Previous studies have
shown that WKYMVm has anti-inflammatory and proresolving effects via activation of the
formyl peptide receptor subtype, FPR2. Since both peptides have short half-lives, in
order to develop peptide analogs as a potential therapeutic, more stable and long-acting
analogs are needed. In this paper, an established MTL/SMAL strategy was used to generate
novel lipidated analogs of WKYMVM and WKYMVm. Both lipidated peptides exhibited enhanced
potency and wash-resistance in cell based assays. The two peptides also showed a potency
shift in the presence of albumin, suggesting adherence to albumin. This is an important
property which has previously been shown to enhance the in vivo half-life of other
lipidated peptides. The current study describes a practical way in which the potency of
both W-peptide enantiomers were enhanced using lipidation, a strategy which may extend
the half-life of the ligands. In summary, we have successfully converted W-peptides into
more promising therapeutic candidates which can be subsequently tested as modulators of
FPR2 in vivo.
Thesis (M.S.)--Tufts University, 2016.
Submitted to the Dept. of Pharmacology & Experimental Therapeutics.
Advisor: Alan Kopin.
Committee: Alan Kopin, and Martin Beinborn.
Keyword: Pharmacology.read less