Gonadotropin-releasing hormone (GnRH) peptides represent an attractive targeting and therapeutic modality due to their receptor overexpression in multiple cancers; however, their clinical translation has been limited by rapid proteolytic degradation, poor membrane permeability, and suboptimal pharmacokinetics. This work presents a systematic medicinal chemistry strategy to address these limitations through progressive molecular engineering of GnRH analogues.
Early approaches focused on glycosylation and lipidation to modulate physicochemical properties. Conjugation of carbohydrate moieties significantly improved enzymatic stability, increasing peptide half-life from minutes to over one hour in biological systems, while maintaining antiproliferative activity in GnRH receptor-positive cancer cells . Lipidation and combined glyco-lipid modification further enhanced membrane interaction and permeability, yielding constructs with improved metabolic stability and direct growth inhibitory effects across multiple tumour cell lines . These studies established a clear relationship between amphiphilicity and biological performance, highlighting the importance of balancing hydrophilic and lipophilic modifications.
Building on these findings, glycolipid GnRH analogues incorporating D-amino acid substitutions and optimised lipid positioning demonstrated enhanced stability, receptor interaction, and direct antiproliferative activity, supporting the role of structural modification in prolonging receptor engagement and improving therapeutic potential .
The culmination of this design strategy is the development of GnRH-modified dendrimer platforms, enabling multivalent presentation and enhanced pharmacological performance. A lipidated tetrameric dendrimer construct exhibited approximately 10-fold improvement in stability and permeability and up to 39-fold increased antiproliferative activity compared to clinically used analogues such as triptorelin, while maintaining comparable gonadotropin-releasing activity . These findings demonstrate that multivalency and controlled molecular architecture can overcome intrinsic limitations of linear peptide therapeutics.
Collectively, this work establishes a structure–stability–activity framework for GnRH-based systems, where targeted chemical modifications—ranging from glycosylation and lipidation to dendrimer-based multivalency—enable the rational design of peptide therapeutics with enhanced stability, bioavailability, and anticancer efficacy. This integrated approach provides a versatile platform for the development of next-generation peptide-based therapeutics.