Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis
Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The development of molecules targeting rhodesain, the main cysteine protease of <i>T. b. rhode...
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MDPI AG
2022-06-01
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| author | Santo Previti Roberta Ettari Carla Di Chio Rahul Ravichandran Marta Bogacz Ute A. Hellmich Tanja Schirmeister Sandro Cosconati Maria Zappalà |
| author_facet | Santo Previti Roberta Ettari Carla Di Chio Rahul Ravichandran Marta Bogacz Ute A. Hellmich Tanja Schirmeister Sandro Cosconati Maria Zappalà |
| author_sort | Santo Previti |
| collection | DOAJ |
| description | Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The development of molecules targeting rhodesain, the main cysteine protease of <i>T. b. rhodesiense</i>, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (<b>SPR10</b>–<b>SPR19</b>) as potential anti-HAT agents. The new molecules show <i>K</i><sub>i</sub> values in the low-micro/sub-micromolar range against rhodesain, coupled with <i>k</i><sub>2nd</sub> values between 1314 and 6950 M<sup>−1</sup> min<sup>−1</sup>. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against <i>T. b. brucei</i> cultures, <b>SPR16</b> and <b>SPR18</b> exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor <b>SPR34</b> highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agents |
| first_indexed | 2024-03-09T22:56:08Z |
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| id | doaj.art-5873f4bdecaa4d6e87e4e4cfc50782cc |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T22:56:08Z |
| publishDate | 2022-06-01 |
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| spelling | doaj.art-5873f4bdecaa4d6e87e4e4cfc50782cc2023-11-23T18:10:54ZengMDPI AGMolecules1420-30492022-06-012712376510.3390/molecules27123765Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African TrypanosomiasisSanto Previti0Roberta Ettari1Carla Di Chio2Rahul Ravichandran3Marta Bogacz4Ute A. Hellmich5Tanja Schirmeister6Sandro Cosconati7Maria Zappalà8Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d’Alcontres 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d’Alcontres 31, 98166 Messina, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d’Alcontres 31, 98166 Messina, ItalyDiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, ItalyInstitute of Organic Chemistry & Macromolecular Chemistry, Friedrich-Schiller-University of Jena, Humboldtstraße 10, 07743 Jena, GermanyInstitute of Organic Chemistry & Macromolecular Chemistry, Friedrich-Schiller-University of Jena, Humboldtstraße 10, 07743 Jena, GermanyInstitute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, GermanyDiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, ItalyDepartment of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d’Alcontres 31, 98166 Messina, ItalyHuman African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by <i>T. b. gambiense</i> and <i>T. b. rhodesiense</i>. The development of molecules targeting rhodesain, the main cysteine protease of <i>T. b. rhodesiense</i>, has led to a panel of inhibitors endowed with micro/sub-micromolar activity towards the protozoa. However, whilst impressive binding affinity against rhodesain has been observed, the limited selectivity towards the target still remains a hard challenge for the development of antitrypanosomal agents. In this paper, we report the synthesis, biological evaluation, as well as docking studies of a series of reduced peptide bond pseudopeptide Michael acceptors (<b>SPR10</b>–<b>SPR19</b>) as potential anti-HAT agents. The new molecules show <i>K</i><sub>i</sub> values in the low-micro/sub-micromolar range against rhodesain, coupled with <i>k</i><sub>2nd</sub> values between 1314 and 6950 M<sup>−1</sup> min<sup>−1</sup>. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against <i>T. b. brucei</i> cultures, <b>SPR16</b> and <b>SPR18</b> exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 µM towards mammalian cells was observed. The discrepancy between rhodesain inhibition and the antitrypanosomal effect could suggest additional mechanisms of action. The biological characterization of peptide inhibitor <b>SPR34</b> highlights the essential role played by the reduced bond for the antitrypanosomal effect. Overall, this series of molecules could represent the starting point for further investigations of reduced peptide bond-containing analogs as potential anti-HAT agentshttps://www.mdpi.com/1420-3049/27/12/3765sleeping sicknessMichael acceptorspeptide backbone modificationsantitrypanosomal agentsrhodesainpseudopeptides |
| spellingShingle | Santo Previti Roberta Ettari Carla Di Chio Rahul Ravichandran Marta Bogacz Ute A. Hellmich Tanja Schirmeister Sandro Cosconati Maria Zappalà Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis Molecules sleeping sickness Michael acceptors peptide backbone modifications antitrypanosomal agents rhodesain pseudopeptides |
| title | Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis |
| title_full | Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis |
| title_fullStr | Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis |
| title_full_unstemmed | Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis |
| title_short | Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis |
| title_sort | development of reduced peptide bond pseudopeptide michael acceptors for the treatment of human african trypanosomiasis |
| topic | sleeping sickness Michael acceptors peptide backbone modifications antitrypanosomal agents rhodesain pseudopeptides |
| url | https://www.mdpi.com/1420-3049/27/12/3765 |
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