Adrenomedullin Receptor Antagonists as Novel Angiogenesis Inhibitors

Le résumé fourni par la source

Adrenomedullin (AM) is a 52 amino acid peptide that belongs to the calcitonin family of peptides. AM is widely expressed throughout the body and plays a critical role in a wide variety of physiological processes including angiogenesis and lymphangiogenesis. AM mediates its effects mainly through the AM1 receptor, which is a receptor complex formed between a family B G protein-coupled receptor (GPCR), the calcitonin receptor-like receptor (CLR) and an accessory protein, receptor activity-modifying protein 2 (RAMP2). AM has been implicated in a number of diseases and most recent attention has focussed on its role in tumour progression, via effects on tumour-associated angiogenesis and lymphangiogenesis. The AM1 receptor is most often implicated in mediating the pro-tumourigenic effects of AM. The most widely used AM receptor antagonist, AM22-52 suffers from only having moderate affinity at the AM1 receptor and lacks selectivity. Thus, the status of the AM1 receptor as a novel and potential target for cancer treatment remains unclear and, high affinity and selective antagonists are needed. This was a dual chemistry and pharmacology thesis that investigated peptide-based AM receptor antagonists. The work arose from previous observations indicating that the extreme C-terminus of AM22-52 is essential for receptor affinity. Thus, structure-activity relationship analysis was performed in this region of AM22-52 with a view to designing AM1 receptor antagonists that exhibit increased affinity at the AM1 receptor. In Chapter three, an Ala scan was conducted on the C-terminal 13 residues of AM22-52 and key residues that were essential for receptor affinity were identified. In Chapter four, short C-terminal fragments were explored as antagonists and AM40-52 was identified as the shortest AM receptor antagonist. In Chapter five, the role of hydrophobicity at the C-terminus of AM22-52 was investigated to help improve AM1 receptor affinity and found that this was not the main physiochemical property for determining receptor selectivity. To examine the efficacy of AM22-52 in a physiologically relevant environment, several models of angiogenesis were set up in Chapter six. Both human AM and AM22-52 failed to elicit the expected effects on the vasculature, suggesting that these models may not be appropriate. The research described in this thesis has produced novel data that contributes to a better understanding on the molecular requirements for binding and receptor selectivity by AM1 receptor antagonists. This information can aid further development of high affinity and selective AM1 receptor antagonists, which can be used as pharmacological tools to help confirm the AM1 receptor as a cancer drug taget.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.