Table 1. Modification strategies used to develop efficacious analogs of G-protein coupled receptor (GPCR) Class II ligands.

Modification strategy	Result of modification	Analog examples
Fatty acid acylation	Increased metabolic stability; enhanced biological activity	Liraglutidea; PEGylated GLP-1b; GIP [mPEG]c
Amino acid substitution	Increased metabolic stability; improvement in bioavailability; enhanced biological activity (agonistic analogs)	I-SAd; Mpr14-rADMe
N-terminal modifications	Increased metabolic stability; enhanced biological activity	[dAla2]GLP-1f
Hybridization (chimera compounds)	Maintained or slightly enhanced biological activity	Glucagon(1-5)GLP-1f; sCT(9-23)-hCT(1-8,24-31)g
Fragmentation	Enhanced biological activity	Pro-Pro-hPTH(1-34)h

Several modification strategies have been employed in order to develop analogs of ligands that bind to Class II GPCRs. These derivatives are designed with the main goals of increasing metabolic stability, improving bioavailability, and enhancing biological activity of their corresponding native peptides. Some examples of these analogs are listed above. Abbreviations used: GLP-1, glucagon-like peptide-1; mPEG, mono-poly(ethylene glycol); GIP, glucose-dependent insulinotropic polypeptide; I-SA, ¹³¹I radioactively-labeled, tyrosine-substituted secretin analog; Mpr14-rADM, mercaptoproprionic acid₍₁₄₎-substituted analog of rat adrenomedullin; dAla₂, D-alanine₍₂₎; sCT, salmon calcitonin; hCT, human calcitonin; Pro-pro-hPTH_(1-34), proline-proline-human parathyroid hormone_(1-34). Subscripted numbers in parentheses indicate the positions of amino acid residues of interest within the native peptide.

^aFeinglos et al., 2005

^bLee et al., 2005

^cGault et al., 2008

^dBanks et al., 2002

^eChampion et al., 1996

^fXiao et al., 2001

^gEpand et al., 2004

^hChunxiao et al., 2007