Chemical modification of class II G protein-coupled receptor ligands: frontiers in the development of peptide analogs as neuroendocrine pharmacological therapies

Abstract

Recent research and clinical data have begun to demonstrate the huge potential therapeutic importance of ligands that modulate the activity of the secretin-like, Class II, G protein-coupled receptors (GPCRs). Ligands that can modulate the activity of these Class II GPCRs may have important clinical roles in the treatment of a wide variety of conditions such as osteoporosis, diabetes, amyotrophic lateral sclerosis and autism spectrum disorders. While these receptors present important new therapeutic targets, the large glycoprotein nature of their cognate ligands poses many problems with respect to therapeutic peptidergic drug design. These native peptides often exhibit poor bioavailability, metabolic instability, poor receptor selectivity and resultant low potencies in vivo. Recently, increased attention has been paid to the structural modification of these peptides to enhance their therapeutic efficacy. Successful modification strategies have included d-amino acid substitutions, selective truncation, and fatty acid acylation of the peptide. Through these and other processes, these novel peptide ligand analogs can demonstrate enhanced receptor subtype selectivity, directed signal transduction pathway activation, resistance to proteolytic degradation, and improved systemic bioavailability. In the future, it is likely, through additional modification strategies such as addition of circulation-stabilizing transferrin moieties, that the therapeutic pharmacopeia of drugs targeted towards Class II secretin-like receptors may rival that of the Class I rhodopsin-like receptors that currently provide the majority of clinically used GPCR-based therapeutics. Currently, Class II-based drugs include synthesized analogs of vasoactive intestinal peptide for type 2 diabetes or parathyroid hormone for osteoporosis.

Figure 1. Role and targets of Class II GPCR ligands in pathophysiology. A large variety of large peptide hormones are secreted that mediate multiple endocrine functions at various target sites

In addition to their physiological role, their pathological secretion or degradation can involve them in multiple acute and chronic disease/pathophysiological processes. The widespread expression and profound activities of these ligands indicate the importance of how a greater understanding of their pharmacological modification may facilitate a new wave of pharmacotherapeutics that may be complementary to or even supersede drugs targeted towards Class I rhodopsin-like receptors.

Figure 2. Chemical modifications of Class II GPCR ligands

The primary chemical modifications applied to Class II GPCR ligands and subsequent analogs are illustrated. A) Amino acid substitution of GHRH-(1-29)-NH₂ within the peptide produces the tetrasubstituted analog CJC-1295 (Teichman et al., 2006). Two amino acid substitutions within the primary sequence of CRH produce the derivative [D-Phe12, Aib15]CRH (Spyroulias et al., 2002). B) Fatty acid acylation of GLP-1 at Lys²⁶ yields the analog liraglutide (Feinglos et al., 2005). C) N-terminal modification of GLP-1-(1-18) at Ala² produces the analog [D-Ala₂]GLP-1-(1-18) (Xiao et al., 2001). D) Chimera formation of the CT derivative sCT-(9-23)-hCT-(1-8, 24-31) occurs by joining segments of hCT and sCT (Epand et al., 2004).