6Y1Q

Cortistatin analog with improved immunoregulatory activity

Summary for 6Y1Q

• Entry DOI: 10.2210/pdb6y1q/pdb
• NMR Information: BMRB: 34491
• Descriptor: Analog 5, OCTANOIC ACID (CAPRYLIC ACID) (2 entities in total)
• Functional Keywords: peptidomimetic, analogue, medical chemistry, hormone
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 1926.37

Authors

Rol, A. (deposition date: 2020-02-13, release date: 2021-01-27, Last modification date: 2024-07-10)

Primary citation

Rol, A.,Todorovski, T.,Martin-Malpartida, P.,Escola, A.,Gonzalez-Rey, E.,Aragon, E.,Verdaguer, X.,Valles-Miret, M.,Farrera-Sinfreu, J.,Puig, E.,Fernandez-Carneado, J.,Ponsati, B.,Delgado, M.,Riera, A.,Macias, M.J.
Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease.
Nat Commun, 12:1869-1869, 2021

PubMed 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.

PubMed: 33767180
DOI: 10.1038/s41467-021-22076-5

Experimental method

SOLUTION NMR