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Current chemotherapy relies on drugs with significant limitations in efficacy and safety, prompting the urgent need to explore innovative approaches to improve the drug discovery pipeline. The unique trypanothione\u2010based redox pathway, which is absent in human hosts, is vital for all trypanosomatids and offers valuable opportunities to guide the rational development of specific, broad\u2010spectrum and innovative anti\u2010trypanosomatid agents. Major efforts focused on the key metabolic enzymes trypanothione synthetase\u2010amidase and trypanothione reductase, whose inhibition should affect the entire pathway and, finally, parasite survival. Herein, we will report and comment on the most recent studies in the search for enzyme inhibitors, underlining the promising opportunities that have emerged so far to drive the exploration of future successful therapeutic approaches.<\/jats:p>","DOI":"10.1002\/cmdc.202000325","type":"journal-article","created":{"date-parts":[[2020,8,28]],"date-time":"2020-08-28T02:24:40Z","timestamp":1598581480000},"page":"2420-2435","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Recent Advancement in the Search of Innovative Antiprotozoal Agents Targeting Trypanothione Metabolism"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-5503","authenticated-orcid":false,"given":"Francesco","family":"Saccoliti","sequence":"first","affiliation":[{"name":"D3 PharmaChemistry Italian Institute of Technology  Via Morego 30 16163 Genova Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4279-7666","authenticated-orcid":false,"given":"Roberto","family":"Di Santo","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco Istituto Pasteur-Fondazione Cenci Bolognetti \u201cSapienza\u201d Universit\u00e0 di Roma  P. le Aldo Moro 5 00185 Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1314-9029","authenticated-orcid":false,"given":"Roberta","family":"Costi","sequence":"additional","affiliation":[{"name":"Dipartimento di Chimica e Tecnologie del Farmaco Istituto Pasteur-Fondazione Cenci Bolognetti \u201cSapienza\u201d Universit\u00e0 di Roma  P. le Aldo Moro 5 00185 Roma Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,9,11]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","unstructured":"Drug for Neglected Disease initiatives DNDi About Leishmaniasis https:\/\/www.dndi.org\/diseasesprojects\/leishmaniasis\/ (accessed April 2020);"},{"key":"e_1_2_7_3_2","unstructured":"Centre of disease control and prevention CDC About Leishmaniasis https:\/\/www.cdc.gov\/parasites\/leishmaniasis\/gen\u2002info\/faqs.html (accessed April 2020);"},{"key":"e_1_2_7_4_2","unstructured":"World health organization WHO Leishmaniasis https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis (accessed April 2020);"},{"key":"e_1_2_7_5_2","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","volume":"392","author":"Burza S.","year":"2018","journal-title":"Lancet"},{"key":"e_1_2_7_6_1","unstructured":"\u00a0"},{"key":"e_1_2_7_7_2","unstructured":"World health organization WHO Chagas Disease (also known as American trypanosomiasis) https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/chagas-disease-(american-trypanosomiasis) (accessed August 2020);"},{"key":"e_1_2_7_8_2","unstructured":"Drug for Neglected Disease initiatives DNDi About Chagas Disease https:\/\/www.dndi.org\/diseases-projects\/chagas\/ (accessed April 2020);"},{"key":"e_1_2_7_9_2","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/S0140-6736(17)31612-4","volume":"391","author":"P\u00e9rez-Molina J. 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