Alanine scan of sialorphin and its hybrids with opiorphin: synthesis, molecular modelling and effect on enkephalins degradation

Małgorzata Sobocińska , Artur Giełdoń , Jakub Fichna , Elżbieta Kamysz


Enkephalins are involved in a number of physiological processes. However, these peptides are quickly degraded by peptidases, e.g. the neutral endopeptidase (NEP). Inhibition of the enzymatic degradation of enkephalins is one of the possible approaches to prolong their activity. Selective inhibitor of NEP, sialorphin, is the attractive lead compound for enkephalins degradation studies. In this work, an alanine scan of sialorphin and a series of its hybrids with opiorphin, synthesised by the solid phase method, were performed. The effect of the peptides on degradation of Met-enkephalin by NEP in vitro was investigated. Molecular modelling technique was used to identify residues responsible for protein–ligand interactions. We showed that substitution of amino acids Gln1, Pro4 and Arg5 of sialorphin for Ala significantly reduced the half-life of Metenkephalin in the presence of NEP. [ Ala3]sialorphin displayed a higher inhibitory potency against NEP than sialorphin. Substitution of His2 for Ala led to a compound which was as active as lead compound. Sialorphin has a structure which hardly tolerates substitution in its sequence at positions 1, 4 and 5. The conversion of His2 for alanine in sialorphin is tolerated very well. The higher inhibitory potency of [ Ala3]sialorphin than sialorphin against NEP is caused by removal of the hydrophilic residue (Asn) and a better fit of the peptide to the enzyme-binding pocket. The role of side chains of sialorphin in degradation of enkephalin by NEP has been explored. This study also provides an important SAR information essential for further drug design.
Author Małgorzata Sobocińska (FCh / DMBt / LChBM)
Małgorzata Sobocińska,,
- Laboratory of Chemistry of Biological Macromolecules
, Artur Giełdoń (FCh / DTCh / LSP)
Artur Giełdoń,,
- Laboratory of Simulation of Polymers
, Jakub Fichna
Jakub Fichna,,
, Elżbieta Kamysz (FCh / DMBt / LChBM)
Elżbieta Kamysz,,
- Laboratory of Chemistry of Biological Macromolecules
Journal seriesAmino Acids, ISSN 0939-4451, (A 30 pkt)
Issue year2018
Publication size in sheets0.5
Keywords in Englishenkephalins, opiorphin, sialorphin, neutral endopeptidase, peptides synthesis, molecular modelling
ASJC Classification1605 Organic Chemistry; 1308 Clinical Biochemistry; 1303 Biochemistry
Languageen angielski
LicenseOther; published final; Uznanie Autorstwa (CC-BY); with publication
Score (nominal)30
ScoreMinisterial score = 30.0, 30-09-2019, ArticleFromJournal
Publication indicators WoS Citations = 0; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 1.042; WoS Impact Factor: 2017 = 2.906 (2) - 2017=2.946 (5)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.