​MELANOCORTIN RECEPTOR AND ENERGY METABOLISM PATHOLOGY

Mainly expressed in the paraventricular nucleus of the hypothalamus, the melanocortin 4 receptor (MC4R) plays a central role in energy homeostasis. Its activation reduces food intake by stimulating the neuronal network of satiety and increases energy expenditure. MC4R deficiency is the most common form of monogenic obesity identified to date. MC4R therefore represents a potential therapeutic target for treating disorders of energy homeostasis, including diseases associated with obesity and cancer cachexia (weight loss with melting of adipose tissue and muscles). Despite extensive research, the identification of endogenous MC4R agonists and antagonists has led to the marketing of only one drug, setmelanotide, an MC4R agonist effective in certain rare forms of severe genetic obesity. It therefore appeared necessary to develop ligands of new origins and structurally different from those of the MC4R.

THE TRAIL OF ANIMAL TOXINS TARGETING MCR4

One solution proposed by the authors is to expand the supply of MC4R ligands by exploring animal venoms, a source of toxins known for their structural diversity and original therapeutic potential. A first screening of the European Venomics toxin library on hMC4R allowed to characterize two candidates: the scorpion toxin N-BUTX-Ptr1a and the spider toxin N-TRTX-Preg1a (see our news of 2020) which possess affinities in the µmolar range for the receptor.
The present work reports the discovery and engineering of a marine cone toxin, N-CTX-Ltg1a, a peptide from a completely new family of toxins unrelated to any other known toxin or melanocortin ligand. The conotoxin identified from the Venomics library screening was derived into a linear peptide HT1-0, which the researchers showed to behave as a competitive antagonist of MC4R with nanomolar affinity, i.e. much better than previous ones.

Unrelated to an endogenous antagonist, the HT1-0 peptide, derived from an animal toxin and presenting a strong affinity for MCR4, opens the way to the development of new antagonists of this receptor which could lead to novel drug candidates, in particular to treat the eating disorders observed in cachexia.

Joliot contact : Nicolas Gilles (nicolas.gilles@cea.fr)

TO GO FURTHER

- A video (in french) on the use of venoms in therapeutic innovation and on the European Venomics bank, held at SIMoS (interview with N Gilles at 3'55'')

- Smartox company website : https://www.smartox-biotech.com/