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A platform‐based approach for peptide drug discovery: generating probes to understand and treat itch (1054.1)
Author(s) -
Doyle Jamie,
Kumar Krishna,
Dong Xinzhong,
Kopin Alan
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1054.1
Subject(s) - peptide , linker , recombinant dna , ligand (biochemistry) , pharmacology , receptor , agonist , transmembrane protein , peptide sequence , g protein coupled receptor , chemistry , drug discovery , biochemistry , biology , computer science , gene , operating system
There is an unmet medical need for novel strategies to treat pruritus (itch). Recently a family of Mas‐related G protein‐coupled receptors (Mrgprs) were cloned and shown to be expressed in primary sensory neurons. Activation of MrgprX1 by the endogenous peptide BAM8‐22 results in histamine independent itch. MrgprX1 is also the target of chloroquine induced itch, a major side effect of this frequently used antimalarial drug. Pharmacological modulators of MrgprX1 are needed as tools to dissect the role of this receptor in mediating pruritus and as candidate therapeutics to combat itch. To define new ligands for MrgprX1, we utilized membrane tethered ligand (MTL) technology. MTLs are recombinant proteins comprised of an extracellular peptide ligand, a linker sequence, and an anchoring transmembrane domain. As MTLs, both BAM8‐22 and γMSH (another peptide ligand of MrgprX1) showed agonist activity. Because of the recombinant nature of MTLs, peptide variants can be rapidly generated and functionally assessed. Using alanine scanning of the two MTLs, we defined specific amino acid positions critical for activity at MrgprX1. With the knowledge gained from these studies, we have begun designing MrgprX1 membrane tethered peptide antagonists. Prior success in converting optimized recombinant MTLs to synthetic lipid anchored peptides provides a roadmap for developing MrgprX1 antagonists as therapeutics for pruritus.