GLP-1 receptor agonist properties of a chimeric peptide derived by hybridization of Latrodectus αLatrotoxin and Heloderma Exendin-4

Chimeric peptides comprised of amino acid sequence motifs found within hormones, neuropeptides, and insect or lizard toxins are now under investigation for their potential use in therapeutics. Here, we report the discovery of one such peptide designated as Black Widow Spider-Exendin-4 (BW-Ex-4). It consists of a putative G protein-coupled receptor (GPCR) binding domain present within αLatrotoxin (αLTX) isolated from Latrodectus, and fused to N- and C- terminal motifs found within the glucagon-like peptide-1 receptor (GLP-1R) agonist Exendin-4 isolated from Heloderma. FRET reporter assays that monitor cAMP production establish BW-Ex-4 to be a specific GLP-1R agonist without any stimulatory action at glucose-dependent insulinotropic peptide (GIP), glucagon, or corticotropin releasing hormone (CRH) receptors. Structural modeling studies of the predicted BW-Ex-4 binding sites at GPCRs of Family B provide new insights concerning the molecular basis for chimeric peptide stimulatory actions at the GLP-1R. We also report that BW-Ex-4 acts in obese hyperglycemic Lepr^db/db mice to suppress appetite, lower body weight, improve glucoregulation, and to reduce circulating levels of pro-inflammatory cytokines. Collectively, these findings establish a combinatorial chimeric peptide chemistry in which αLTX serves as a molecular scaffold for the design of hybrid peptides with novel GPCR stimulating properties.