{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T17:38:51Z","timestamp":1789925931318,"version":"4.0.1"},"reference-count":232,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2024,12,28]],"date-time":"2024-12-28T00:00:00Z","timestamp":1735344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Plasmodium, Leishmania, and Trypanosoma parasites are responsible for infectious diseases threatening millions of people worldwide. Despite more recent efforts devoted to the search for new antiprotozoal agents, efficacy, safety, and resistance issues still hinder the development of suited therapeutic options. The lack of robustly validated targets and the complexity of parasite\u2019s diseases have made phenotypic screening a preferential drug discovery strategy for the identification of new chemical entities. However, via this approach, no information on biological target(s) and mechanisms of action of compounds are provided. Among the target deconvolution strategies useful to fill this gap, photoaffinity labeling (PAL) has emerged as one of most suited to enable investigation in a complex cellular environment. More recently, PAL has been exploited to unravel the molecular basis of bioactive compounds\u2019 function in live parasites, allowing elucidation of the mechanism of action of both approved drugs and new chemical entities. Besides highlighting new potential drug targets, PAL can provide valuable information on efficacy and liabilities of small molecules at the molecular level, which could be exploited to greatly facilitate the rational optimization of compounds in terms of potency and safety. In this review, we will report the most recent studies that have leveraged PAL to disclose the biological targets and mechanism of action of phenotypically active compounds targeting kinetoplastid diseases (i.e., human African trypanosomiasis, leishmaniasis, and Chagas disease) and malaria. Moreover, we will comment on potential perspectives that this innovative approach can provide in aiding the discovery and development of new antiprotozoal drugs.<\/jats:p>","DOI":"10.3390\/ph18010028","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T10:17:40Z","timestamp":1735640260000},"page":"28","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5291-0837","authenticated-orcid":false,"given":"Alessandro","family":"Giraudo","sequence":"first","affiliation":[{"name":"Dipartimento di Scienze Farmaceutiche, Universit\u00e0 degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6726-9501","authenticated-orcid":false,"given":"Cristiano","family":"Bolchi","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmaceutiche, Universit\u00e0 degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Pallavicini","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze Farmaceutiche, Universit\u00e0 degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, 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, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"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, I-00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2907-5503","authenticated-orcid":false,"given":"Francesco","family":"Saccoliti","sequence":"additional","affiliation":[{"name":"Dipartimento di Scienze della Vita, della Salute e delle Professioni Sanitarie, Universit\u00e0 degli Studi \u201cLink Campus University\u201d, Via del Casale di S. 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