Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid
Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates we...
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MDPI AG
2022-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/18/10839 |
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| author | Barbara Żyżyńska-Granica Adriano Mollica Azzurra Stefanucci Sebastian Granica Patrycja Kleczkowska |
| author_facet | Barbara Żyżyńska-Granica Adriano Mollica Azzurra Stefanucci Sebastian Granica Patrycja Kleczkowska |
| author_sort | Barbara Żyżyńska-Granica |
| collection | DOAJ |
| description | Chemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates were presented that combine both opioid and neurotensin pharmacophores in one entity, thus generating a hybrid compound. Importantly, these chimeras are structurally similar except for an amino acid change at position 9 of the peptide chain. In fact, isoleucine (C<sub>6</sub>H<sub>13</sub>NO<sub>2</sub>) was replaced with its isomer <i>tert</i>-leucine. These may further lead to various differences in hybrids’ behavior under specific conditions (temperature, UV, oxidative, acid/base environment). Therefore, the purpose of the study is to assess and compare the chemical stability of two hybrid peptides that differ in nature by way of one amino acid (<i>tert</i>-leucine vs. isoleucine). The obtained results indicate that, opposite to biological activity, the substitution of <i>tert</i>-leucine into isoleucine did not substantially influence the compound’s chemical stability. In fact, neither hydrolysis under alkaline and acidic conditions nor oxidative degradation resulted in spectacular differences between the two compounds—although the number of potential degradation products increased, particularly under acidic pH. However, such a modification significantly reduced the compound’s half-life from 204.4 h (for PK20 exposed to 1M HCl) to 117.7 h for [Ile<sup>9</sup>]PK20. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T23:42:36Z |
| publishDate | 2022-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-1cd88764b9fb4bd3868fb759058dcdc42023-11-23T16:48:53ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-09-0123181083910.3390/ijms231810839Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino AcidBarbara Żyżyńska-Granica0Adriano Mollica1Azzurra Stefanucci2Sebastian Granica3Patrycja Kleczkowska4Chair and Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, 02-097 Warsaw, PolandDepartment of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyDepartment of Pharmacy, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyMicrobiota Lab, Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, 02-097 Warsaw, PolandMilitary Institute of Hygiene and Epidemiology, 01-163 Warsaw, PolandChemical stability is one of the main problems during the discovery and development of potent drugs. When ignored, it may lead to unreliable biological and pharmacokinetics data, especially regarding the degradation of products’ possible toxicity. Recently, two biologically active drug candidates were presented that combine both opioid and neurotensin pharmacophores in one entity, thus generating a hybrid compound. Importantly, these chimeras are structurally similar except for an amino acid change at position 9 of the peptide chain. In fact, isoleucine (C<sub>6</sub>H<sub>13</sub>NO<sub>2</sub>) was replaced with its isomer <i>tert</i>-leucine. These may further lead to various differences in hybrids’ behavior under specific conditions (temperature, UV, oxidative, acid/base environment). Therefore, the purpose of the study is to assess and compare the chemical stability of two hybrid peptides that differ in nature by way of one amino acid (<i>tert</i>-leucine vs. isoleucine). The obtained results indicate that, opposite to biological activity, the substitution of <i>tert</i>-leucine into isoleucine did not substantially influence the compound’s chemical stability. In fact, neither hydrolysis under alkaline and acidic conditions nor oxidative degradation resulted in spectacular differences between the two compounds—although the number of potential degradation products increased, particularly under acidic pH. However, such a modification significantly reduced the compound’s half-life from 204.4 h (for PK20 exposed to 1M HCl) to 117.7 h for [Ile<sup>9</sup>]PK20.https://www.mdpi.com/1422-0067/23/18/10839hybrid peptidesstabilitydegradationchemical structure |
| spellingShingle | Barbara Żyżyńska-Granica Adriano Mollica Azzurra Stefanucci Sebastian Granica Patrycja Kleczkowska Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid International Journal of Molecular Sciences hybrid peptides stability degradation chemical structure |
| title | Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid |
| title_full | Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid |
| title_fullStr | Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid |
| title_full_unstemmed | Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid |
| title_short | Comparative Study of Chemical Stability of a PK20 Opioid–Neurotensin Hybrid Peptide and Its Analogue [Ile<sup>9</sup>]PK20—The Effect of Isomerism of a Single Amino Acid |
| title_sort | comparative study of chemical stability of a pk20 opioid neurotensin hybrid peptide and its analogue ile sup 9 sup pk20 the effect of isomerism of a single amino acid |
| topic | hybrid peptides stability degradation chemical structure |
| url | https://www.mdpi.com/1422-0067/23/18/10839 |
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