Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease

Álvaro Rol, Toni Todorovski, Pau Martin-Malpartida, Anna Escolà, Elena Gonzalez-Rey, Eric Aragón, Xavier Verdaguer, Mariona Vallès-Miret, Josep Farrera-Sinfreu, Eduard Puig, Jimena Fernández-Carneado, Berta Ponsati, Mario Delgado (), Antoni Riera () and Maria J. Macias ()
Additional contact information
Álvaro Rol: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Toni Todorovski: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Pau Martin-Malpartida: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Anna Escolà: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Elena Gonzalez-Rey: Instituto de Parasitologia y Biomedicina López-Neyra (IPBLN-CSIC)
Eric Aragón: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Xavier Verdaguer: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Mariona Vallès-Miret: BCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars
Josep Farrera-Sinfreu: BCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars
Eduard Puig: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Jimena Fernández-Carneado: BCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars
Berta Ponsati: BCN Peptides S.A. Pol.Ind. Els Vinyets-Els Fogars
Mario Delgado: Instituto de Parasitologia y Biomedicina López-Neyra (IPBLN-CSIC)
Antoni Riera: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology
Maria J. Macias: Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Ulcerative colitis and Crohn’s disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.

Date: 2021
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DOI: 10.1038/s41467-021-22076-5

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