Potent trypsin-resistant hGH-RH analogues

Area of Science:

• Medicinal Chemistry
• Peptide Synthesis
• Endocrinology

Background:

• Human growth hormone-releasing hormone (hGH-RH) plays a crucial role in regulating growth hormone secretion.
• Native hGH-RH-(1-29)-NH2 is susceptible to degradation, limiting its therapeutic potential.
• Developing metabolically stable analogues is key for effective hormone replacement therapy.

Purpose of the Study:

• To synthesize and characterize novel analogues of hGH-RH-(1-29)-NH2 with improved metabolic stability.
• To evaluate the in vivo potency and stability of these modified peptides.
• To identify potential candidates for the clinical treatment of growth hormone deficiency.

Main Methods:

• Solid-phase peptide synthesis (SPPS) using a modified Boc strategy.
• Incorporation of unnatural amino acids and post-assembly guanidinylation of side chains.
• Assessment of enzymatic stability (trypsin resistance) and in vivo potency in a rat model.

Main Results:

• Synthesized analogues ([Dat1, Har(11, 12, 20, 21, 29), Ala15, Nle27, Asp28]-, [Dat1, Har(11, 20, 29), Orn12, Ala15, Nle27, Asp28]-, and [Dat1, Gap(11,12, 21, 29), Ala15, Har20, Nle27, Asp28]-hGH-RH-(1-29)-NH2) demonstrated complete resistance to trypsin.
• These analogues exhibited approximately 50-fold higher potency compared to native hGH-RH-(1-29)-NH2 in subcutaneous injection studies in rats.
• The modifications successfully enhanced metabolic stability and biological activity.

Conclusions:

• The synthesized hGH-RH analogues possess significant metabolic stability and increased potency.
• These modified peptides represent promising candidates for therapeutic applications in treating growth hormone deficiency.
• Further clinical evaluation is warranted to confirm their efficacy and safety in humans.