Current hormone substitution therapy of patients with congenital adrenal hyperplasia (CAH) is suboptimal and cannot mimic physiological daily rhythms of hormone secretion. As supra-physiological corticoid doses are necessary to avoid adrenal androgen excess, patients show substantially increased comorbidities such as hyperglycemia, arterial hypertension, reduced growth and osteoporosis. Moreover plasma ACTH is often inadequately suppressed, resulting in undesired excess adrenal androgen production causing accelerated bone maturation, virilisation and early puberty. This therapeutic situation is unsatisfactory and demands innovative treatment options. At present there is no effective medical treatment that would directly block the action of ACTH at the highly selective melanocortin 2 receptor (MC2R). Such a therapy would be of great clinical value allowing a strategy of blocking ACTH action and replacing with physiological hydrocortisone doses.
The aim of our study is to inhibit ACTH binding and signal transduction by blocking the MC2R stimulation with potent and selective antagonist peptides. Different newly synthesized peptides were investigated for antagonist activity on MC2R in stably transfected human embryonic kidney cells (HEK293) and in the human adrenal tumor cell line NCI-295RA. These peptides show a high structure homology to ACTH as they have the same binding motif but different modifications in the activation motif. Three peptides reduced ACTH-stimulated MC2R activity indicated by a reduced cAMP response in vitro. Cells pre-incubated with the peptidomimetic LNP009 showed the most efficient blockade of the MC2R and a reduced expression of the steroidogenic enzymes CYP21A2, CYP11B1 and HSD3B2, while having no antagonistic effect up to 1 µM at MC3, MC4, or MC5 receptors. Further peptides are currently developed and tested in our cell systems which are chemically optimized by incorporation of synthetic non-natural amino acid components.
In conclusion we present three peptide antagonists blocking the MC2R pathway, which could be a promising treatment approach for CAH patients. The ultimate goal is to offer patients a novel treatment strategy lacking the side effects of the currently used ACTH-suppressing corticoid therapy.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology