Structure-based design of a Cortistatin analog with improved immunoregulatory activity against inflammatory bowel disease (IBD)

Abstract

Ulcerative colitis and Crohn's disease are inflammatory bowel diseases (IBD) that lead to chronic inflammations of the gastrointestinal tract due to an abnormal response of the immune system. Finding new effective drugs to tackle IBD represents a major therapeutic concern since IBD incidence and prevalence is increasing worldwide. Recent studies positioned Cortistatin (CST) as a candidate for IBD treatment due to its anti-inflammatory and immunomodulatory activity. Here, we studied the structural properties of CST using NMR and synthesized and characterized new analogs displaying enriched populations of some native conformations. One of them, Analog 5, preserved the activity against IBD with an increased half-life in serum, overcoming the native hormone limitation and opening the door for the use of CST analogs as therapeutic agents. This work represents a new approach to the rational design of molecules to treat IBD and a possibility for patients that fail to respond to other therapies.

Protective role of cortistatin in pulmonary inflammation and fibrosis

“…It is important mentioning that cortistatin has a favourable safety profile in humans and demonstrated clinical efficiency in patients with Cushing's disease (Giordano et al, 2007). Furthermore, the interest of the pharmaceutical companies in developing cortistatin-based analogues with improved half-life in serum has increased lately, and a recent report demonstrated their efficiency in inflammatory conditions (Rol et al, 2021). We have recently assisted to an example of repositioning of a therapy based in another immunomodulatory and anti-fibrotic neuropeptide, vasoactive intestinal peptide or Aviptadil (Chorny and Delgado, 2008;Prasse et al, 2010), for the treatment of ARDS in patients with severe covid-19 (Scavone et al, 2020;clinical trial: NCT04311697).…”