## 1 Introduction  
Inflammatory bowel diseases (IBDs), which consist primarily of [PERSON]'s disease (CD) and ulcerative colitis (UC), are a group of idiopathic inflammatory conditions occurring in the small intestine and the colon. The etiology of IBDs has not been revealed to date, however, it is thought to be a combination of genetic, environmental and immunological factors contributing to the pathologic reaction of the immune system in the gut [1; 2]. In the course of IBDs, the excessive activation of the immune system is observed, which results in an enhanced secretion of pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF\(\alpha\)), and an imbalance in the levels of pro- and anti-inflammatory factors in the tissue [3] which is responsible for the occurrence of clinical symptoms of the disease, e.g., inflammation of the intestinal mucosa or visceral pain. The major therapeutic goals in IBD patients are the control of inflammation and the treatment of clinical symptoms such as diarrhea and rectal bleeding [4]. One of the natural sources for anti-IBD drugs is the human body, which produces endogenous opioids, enkephalins. Met-enkephalin (YGGFM) and Leu-enkephalin (YGGFL) participate in the antinociception [5], the regulation of gastrointestinal motility [5], the modulation of the immune system [6; 7] and affecting anti-inflammatory, hormonal and behavioral responses [8]. Since they are natural products, they are prone to fast degradation and loss of activity. Aminopeptidase N (APN), neutral endopeptidase (NEP), dipeptidyl peptidase III (DPP III) and angiotensin converting enzyme (ACE) are the major enkephalin-degrading enzymes [9; 10]. These proteases are widely distributed in the human body and are significantly involved in physiological modulation and pathophysiological processes in the gastrointestinal tract [11]. The indirect stimulation of opioid receptors by the blockade of NEP and APN is a promising pharmacological strategy for the treatment of IBDs and may become of greater importance than the use of classical opioid agonists. Rat sialorphin (QHNPR), human opiorphin (QRFSR) and bovine spinorphin (LVVYPWT) are endogenous inhibitors of enkephalin-degrading enzymes. Studies have confirmed their efficacy in blocking the activity of enkephalinase both in vitro and in vivo. It has been demonstrated that these inhibitors possess a strong analgesic, anti-inflammatory, immunological and metabolic effect, either directly or indirectly, by affecting the level of enkephalins [12; 13; 14; 15; 16; 17]. The significant limitation on the use of opiorphin, sialorphin and spinorphin in systemic therapeutic applications is the rapid degradation of their peptide bonds by circulating peptidases. In addition, in sialorphin and opiorphin, there is an issue with the stability of the \(N\)-terminal glutamine residue, which can be converted into a cyclic structure called pyroglutamine (Glp) in the body fluids at pH \(<\) 7 [18; 19]. The metabolic half-life of native opiorphin in human plasma was evaluated at 5 min [20]. Its disappearance results in part from the cyclization of Gln\({}^{1}\) to Glp (16% maximum) but mainly from the hydrolytic removal of both Gln\({}^{1}\) and Glp\({}^{1}\) peptides by plasma amino peptidases. The small amount of opiorphin (12%) disappears because of potential complex formation [20]. Sialorphin is also sensitive to degradation in human plasma [21]. Several modifications could help improve the metabolic stability of peptides, for instance: protecting the \(N\)-terminal amino group by \(N\)-acetylation and \(C\)-terminal carboxyl group by amidation, the selective substitution of amino acids with non-natural amino acids, the replacement of the \(N\)- and \(C\)-terminal amino acid residues by their respective d-enantiomer or \(\beta\)-amino acid, designing pseudo peptides or creating dimeric forms.