Abstract
Inflammatory bowel diseases are a set of complex and debilitating diseases, for which there is no satisfactory treatment. Peptides as small as three amino acids have been shown to have anti-inflammatory activity in mouse models of colitis, but they are likely to be unstable, limiting their development as drug leads. Here, we have grafted a tripeptide from the annexin A1 protein into linaclotide, a 14-amino-acid peptide with three disulfide bonds, which is currently in clinical use for patients with chronic constipation or irritable bowel syndrome. This engineered disulfide-rich peptide maintained the overall fold of the original synthetic guanylate cyclase C agonist peptide, and reduced inflammation in a mouse model of acute colitis. This is the first study to show that this disulfide-rich peptide can be used as a scaffold to confer a new bioactivity.
Highlights
Peptides display a range of potentially useful biological functions such as anti-inflammatory [1], anti-cancer [2], anti-HIV [3], antimicrobial [4], and insecticidal [5] activities, among others
To confirm that the fold of the synthetic peptides was similar to related peptides, and likely to have the native disulfide connectivity, we compared the secondary shifts to STh (6-19), which is a toxin that only differs from linaclotide by one residue; linaclotide contains a tyrosine at residue 4, whereas STh (6-19) contains a leucine
We show for the first time that the highly disulfide-rich peptide, linaclotide, can be used as a scaffold to confer anti-inflammatory activity in a TNBS mouse model of colitis
Summary
Peptides display a range of potentially useful biological functions such as anti-inflammatory [1], anti-cancer [2], anti-HIV [3], antimicrobial [4], and insecticidal [5] activities, among others. MVIIA and is currently used for the treatment of chronic pain [8] This cone-snail venom peptide is a calcium channel antagonist, containing 25 residues and three disulfide bonds in a cystine knot motif [9]. Linaclotide, a 14-amino-acid peptide with three disulfide bonds, interacts with guanylate cyclase-C, generating cyclic guanosine monophosphate (cGMP), and is currently in clinical use for patients with chronic constipation or irritable bowel syndrome [10]. Linaclotide is administered orally and improves bowel function and abdominal discomfort [11] These three peptides are constrained either by a cyclic backbone or disulfide bonds, highlighting the advantages of using covalent constraints to improve the therapeutic potential of peptides. To further explore the potential of using disulfide-rich/cyclic peptide scaffolds for IBD applications, we have used the linaclotide scaffold for grafting the MC-12 sequence. Linaclotide regulates guanylate cyclase C (GCC) and is used in the treatment of irritable bowel syndrome (IBS), but has not been demonstrated to regulate autoimmune diseases such as inflammatory bowel disease (IBD), making this study the first to examine its potential as a scaffold in IBD
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