{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T14:58:33Z","timestamp":1791644313833,"version":"4.3.4"},"reference-count":83,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,11]],"date-time":"2022-06-11T00:00:00Z","timestamp":1654905600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FFABR 2020 of the University of Messina","award":["390713860"],"award-info":[{"award-number":["390713860"]}]},{"name":"Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)","award":["390713860"],"award-info":[{"award-number":["390713860"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Human African Trypanosomiasis (HAT) is an endemic protozoan disease widespread in the sub-Saharan region that is caused by T. b. gambiense and T. b. rhodesiense. The development of molecules targeting rhodesain, the main cysteine protease of T. b. rhodesiense, 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 (SPR10\u2013SPR19) as potential anti-HAT agents. The new molecules show Ki values in the low-micro\/sub-micromolar range against rhodesain, coupled with k2nd values between 1314 and 6950 M\u22121 min\u22121. With a few exceptions, an appreciable selectivity over human cathepsin L was observed. In in vitro assays against T. b. brucei cultures, SPR16 and SPR18 exhibited single-digit micromolar activity against the protozoa, comparable to those reported for very potent rhodesain inhibitors, while no significant cytotoxicity up to 70 \u00b5M 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 SPR34 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<\/jats:p>","DOI":"10.3390\/molecules27123765","type":"journal-article","created":{"date-parts":[[2022,6,12]],"date-time":"2022-06-12T22:37:20Z","timestamp":1655073440000},"page":"3765","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Development of Reduced Peptide Bond Pseudopeptide Michael Acceptors for the Treatment of Human African Trypanosomiasis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8473-3321","authenticated-orcid":false,"given":"Santo","family":"Previti","sequence":"first","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9020-2068","authenticated-orcid":false,"given":"Roberta","family":"Ettari","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3191-3932","authenticated-orcid":false,"given":"Carla","family":"Di Chio","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d\u2019Alcontres 31, 98166 Messina, Italy"},{"name":"Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahul","family":"Ravichandran","sequence":"additional","affiliation":[{"name":"DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Bogacz","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry & Macromolecular Chemistry, Friedrich-Schiller-University of Jena, Humboldtstra\u00dfe 10, 07743 Jena, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ute A.","family":"Hellmich","sequence":"additional","affiliation":[{"name":"Institute of Organic Chemistry & Macromolecular Chemistry, Friedrich-Schiller-University of Jena, Humboldtstra\u00dfe 10, 07743 Jena, Germany"},{"name":"Centre for Biomolecular Magnetic Resonance (BMRZ), Goethe University Frankfurt, Max von Laue Str. 9, 60438 Frankfurt, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanja","family":"Schirmeister","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical and Biomedical Sciences, University of Mainz, Staudingerweg 5, 55128 Mainz, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8900-0968","authenticated-orcid":false,"given":"Sandro","family":"Cosconati","sequence":"additional","affiliation":[{"name":"DiSTABiF, University of Campania Luigi Vanvitelli, Via Vivaldi 43, 81100 Caserta, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Zappal\u00e0","sequence":"additional","affiliation":[{"name":"Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Stagno d\u2019Alcontres 31, 98166 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,11]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022, April 10). 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