Peptide Structure-Activity Insights Reveal Keys to Growth Hormone Secretagogue Potency

Growth hormone (GH) plays a crucial role in growth, metabolism, and body composition. Growth hormone secretagogues (GHS) are compounds that stimulate the body's natural release of GH, offering therapeutic potential for conditions like GH deficiency, frailty, and sarcopenia. Despite the therapeutic promise, a comprehensive understanding of the precise structural features that dictate the potency and selectivity of peptidic GHS has remained elusive, hindering rational drug design.

The study revealed critical structural determinants for GHS activity, identifying specific residues essential for receptor binding and activation. Substitution of a hydrophobic amino acid at position 4 with a polar residue consistently led to a >90% reduction in GH-releasing activity in vitro (p<0.001). The most significant finding was that the introduction of a D-amino acid at position 2 of the lead peptide resulted in a 3.2-fold increase in in vivo GH secretion compared to the parent compound (p<0.01) at the 0.1 mg/kg dose. Furthermore, modifications to the C-terminus significantly impacted peptide stability, with a C-terminal amide modification extending the in vivo half-life by approximately 50% without compromising potency. Overall, three novel analogs demonstrated superior potency, achieving comparable or greater GH release at 5-fold lower concentrations than the original lead peptide.