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Detail of the key contacts between amino acids (in yellow) that define the characteristics of the active analogue (Image: IRB Barcelona).

Towards an innovative treatment for Crohn’s disease and ulcerative colitis

Scientists from the Institute for Research in Biomedicine (IRB Barcelona) at the Barcelona Science Park have participated in research to identify and study an analogue of the natural peptide hormone cortistatin -a molecule with a powerful anti-inflammatory and modulating effect on the immune respons- as a potential drug for the treatment of inflammatory bowel disease. The results have been published in the journal Nature Communications.

The study has been co-lead by Dr Maria Macias and Dr Antoni Riera, group leaders at IRB Barcelona; Dr. Mario Delgado, head of the Neuroimmunology of Inflammatory and Autoimmune Diseases group at the Instituto de Parasitología y Biomedicina López Neyra (IPBLN), and Dr Jimena Fernández and Dr Berta Ponsati from BCN Peptides.

Inflammatory bowel disease describes a family of disorders that includes Crohn’s disease and ulcerative colitis, conditions that affect more than 300,000 people in Spain.  The origin is unknown. Although there is currently no cure, some treatments are available to alleviate symptoms. “Inflammatory bowel disease is increasingly being detected in young people and, depending on its severity, can be incapacitating,” explains Dr.Macias, ICREA researcher and head of the Structural Characterization of Macromolecular Assemblies lab at IRB Barcelona.

The cortistatin analogue selected as a potential drug is in the clinical development phase and is expected to be commercialised shortly.

A new interdisciplinary approach

Somatostatin and cortistatin are natural peptide hormones with very short half-lives that exert many biological effects. The research groups headed by Dr Macias and Dr Riera have studied how to stabilise these peptides and make them more selective. Specifically, cortistatin is considered a neuropeptide. The unique chemical structure and powerful biological activity of this compound have stimulated interest in its total synthesis and subsequent biological evaluation.

To design a more stable cortistatin analogue, IRB Barcelona researchers studied the structure of this hormone by means of nuclear magnetic resonance and used the information obtained as a guide to prepare other peptides with similar structures. “The idea was to optimise the stability of cortistatin analogues for pharmacological use while maintaining a structure and activity like that of the native peptide,” explains Dr Riera, head of the Research Unit on Asymmetric Synthesis at IRB Barcelona and professor in the Department of Inorganic and Organic Chemistry at the University of Barcelona.

To prepare a series of cortistatin analogues, the experience of the company BCN Peptides and that of the laboratories of Dr Riera and Dr Macias in the design and synthesis of peptides and in structural studies using nuclear magnetic resonance imaging, respectively, was pooled.

In collaboration with Dr. Delgado, the efficacy of the cortistatin analogues was evaluated in preclinical models of inflammatory bowel disease. “We have identified and developed a peptide that is ten times more stable in plasma than cortistatin and that exerts anti-inflammatory activity superior to that shown by some treatments already approved for Crohn’s disease,” explain Dr Delgado from IPBLN-CSIC and Drs Fernández and Ponsati from BCN peptides.

» Reference article: Álvaro Rol, Toni Todorovski, Pau Martin-Malpartida, Anna Escolà, Elena Gonzalez-Rei, Eric Aragó, Xavier Verdaguer, Mariona Vallès-Miret, Josep Farrera-Sinfreu, Eduard Puig, Jimena Fernández-Carneado, Berta Ponsati, Mario Delgado, Antoni Riera & Maria J. Macias. “Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease”. Nature Communications (2021) DOI: 10.1038 / s41467-021-22076-5

» For further information: IRB Barcelona website [+]