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

Abstract

Ulcerative colitis and Crohns 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. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=105 SRC="FIGDIR/small/839787v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@b84405org.highwire.dtl.DTLVardef@179d0bdorg.highwire.dtl.DTLVardef@775736org.highwire.dtl.DTLVardef@fea7cd_HPS_FORMAT_FIGEXP M_FIG C_FIG