Cyclic galanin-analogs and uses thereof

Abstract

The invention generally relates to the field of medicine and pharmacology. More particularly, it relates to novel analogs of galanin, and the use thereof in therapy. Provided is a cyclic peptide analog of galanin, wherein the galanin analog comprises a (methyl)Lanthionine bridge and wherein the analog has the general formula “X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-”, or a truncated variant thereof lacking X1 and/or up to 11 of the C-terminal residues, wherein two residues selected from the group consisting of X3, X4, X6, X7, X10 and X13-X19 together form a Lanthionine bridge of the structure Ala-S-Ala, or a methylLanthionine bridge of the structure Abu-S-Ala or Ala-S-Abu.

What is claimed is: 
     
         1 . An isolated nucleic acid sequence encoding a peptide selected from the group consisting of 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 58) 
                 
                     
                   GWNTNACGYLLGPHAVGNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 59) 
                 
                     
                   GWNTNACGYLLGPHAVGNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 60) 
                 
                     
                   GWNLNAATYLCGPHAVGNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 61) 
                 
                     
                   GWNLNAATYLCGPHAVGNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 62) 
                 
                     
                   GWNLNAASYLLCGPHAVGNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 63) 
                 
                     
                   GWNLNAASYLLCGPHAVGNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 64) 
                 
                     
                   GWNLNAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 65) 
                 
                     
                   GWNLNAAGYLLGATAVCNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 66) 
                 
                     
                   GWNLNAAGYLLGASAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 67) 
                 
                     
                   GWNLNAAGYLLGASAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 68) 
                 
                     
                   GWNLNAAGYLLGASAVCNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 69) 
                 
                     
                   GWNLNAAGYLLGATAVGCHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 70) 
                 
                     
                   GWNLNAAGYLLGASAVGC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 71) 
                 
                     
                   GWNLNAAGYLLGASAVGCHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 72) 
                 
                     
                   GWNLNAAGYLLGASAVGNCR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 73) 
                 
                     
                   GWNLNAAGYLLGASAVGNC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 74) 
                 
                     
                   GWNLNAAGYLLGASAVGNHC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 75) 
                 
                     
                   GWNLNAAGYLLGPHTVGCHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 76) 
                 
                     
                   GWNLNAAGYLLGPHSVGC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 77) 
                 
                     
                   GWNLNAAGYLLGPHATGNCR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 78) 
                 
                     
                   GWNLNAAGYLLGPHASGNC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 74) 
                 
                     
                   GWNLNAAGYLLGASAVGNHC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 79) 
                 
                     
                   QWNLNAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 80) 
                 
                     
                   QWNLNAAGYLLGATAVCNH 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 81) 
                 
                     
                   QWNLNAAGYLLGASAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 82) 
                 
                     
                   QWNLNAASYLLC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 83) 
                 
                     
                   QWNLNAAGYLLGPHTVGCHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 84) 
                 
                     
                   GWNLNAAGYLLGTHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 85) 
                 
                     
                   GWNLNAAGYLLGPTAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 86) 
                 
                     
                   GWNLNAAGYLLATHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 87) 
                 
                     
                   GWNLNAAGYLLGATAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 88) 
                 
                     
                   QWNLNAAGYLLATHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 93) 
                 
                     
                   QWNLNAAGYLLGATAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 90) 
                 
                     
                   QWNLNAAGYLLASHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 91) 
                 
                     
                   QWNLNAAGYLLATHACGNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 60) 
                 
                     
                   GWNLNAATYLCGPHAVGNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 92) 
                 
                     
                   QWNLNAAGYLLGPHATGNCR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 86) 
                 
                     
                   GWNLNAAGYLLATHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 88) 
                 
                     
                   QWNLNAAGYLLATHACG 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 87) 
                 
                     
                   GWNLNAAGYLLGATAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 93) 
                 
                     
                   QWNLNAAGYLLGATAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 94) 
                 
                     
                   GWNVNAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 95) 
                 
                     
                   GWNDNAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 96) 
                 
                     
                   GWNNNAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 97) 
                 
                     
                   GWNLVAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 98) 
                 
                     
                   GWNLKAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 99) 
                 
                     
                   GWNLDAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 100) 
                 
                     
                   GWNLQAAGYLLGATAVCNHR 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 103) 
                 
                     
                   QWNLNAAGYLLGPSAVC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 104) 
                 
                     
                   QWTLNAASYLLC 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 101) 
                 
                     
                   QWNLNAAGYLLGPTAVC 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 102) 
                 
                     
                   QWTLNAATYLLC. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         2 . A vector comprising an isolated nucleic acid sequence according to  claim 1 , wherein said nucleic acid is genetically fused to a nucleic acid sequence encoding a lanthipeptide-leader sequence. 
     
     
         3 . A food-grade bacterial host cell comprising a vector according to  claim 2 . 
     
     
         4 . The food-grade bacterial host cell of  claim 3  comprising a  L. lactis  host cell. 
     
     
         5 . The food-grade bacterial host cell of  claim 3  further comprising lanthionine introduction enzymes. 
     
     
         6 . An oral delivery system for production of lanthi-galanins in the gut, said s system comprising the food-grade bacterial host cell of  claim 3 . 
     
     
         7 . A pharmaceutical composition comprising viable host cells according to  claim 3  and a pharmaceutically acceptable carrier, diluent or vehicle. 
     
     
         8 . The pharmaceutical composition of  claim 7  formulated for oral administration. 
     
     
         9 . A method of treating or alleviating symptoms associated with inflammatory bowel disease, said method comprising administering to a subject in need thereof a pharmaceutical composition according to  claim 7 . 
     
     
         10 . The method of  claim 9  wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis (UC).