Receptors for chemotactic formyl peptides as pharmacological targets

Leukocytes accumulate at sites of inflammation and immunological reaction in response to locally existing chemotactic mediators. N-formyl peptides, such as fMet-Leu-Phe (fMLF), are some of the first identified and most potent chemoattractants for phagocytic leukocytes. In addition to the bacterial peptide fMLF and the putative endogenously produced formylated peptides, a number of novel peptide agonists have recently been identified that selectively activate the high- affinity fMLF receptor FPR and/or its low-affinity variant FPRLI, both of which belong to the seven-transmembrane (STM), G protein-coupled receptor (GPCR) superfamily. These agonists include peptide domains derived from the envelope proteins of human immunodeficiency virus type 1 (HIV-1) and at least three amyloidogenic polypeptides, the human acute phase protein serum amyloid A, the 42 amino acid form of beta amyloid peptide and a 21 amino acid fragment of human prion. Furthermore, a cleavage fragment of neutrophil granule-derived bactericidal cathelicidin, LL-37, is also a chemotactic agonist for FPRLI. Activation of formyl peptide receptors results in increased cell migration, phagocytosis, release of proinflammatory mediators, and the signaling cascade culminates in heterologous desensitization of other STM receptors including chemokine receptors CCR5 and CXCR4, two coreceptors for HIV-1. Thus, by interacting with a variety of exogenous and host-derived agonists, formyl peptide receptors may play important roles in proinflammatory and immunological diseases and constitute a novel group of pharmacological targets. Published by Elsevier Science B.V.

See More