Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy
<i>Plasmodium</i>, <i>Leishmania</i>, and <i>Trypanosoma</i> 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 resistanc...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Pharmaceuticals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1424-8247/18/1/28 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832587709943644160 |
|---|---|
| author | Alessandro Giraudo Cristiano Bolchi Marco Pallavicini Roberto Di Santo Roberta Costi Francesco Saccoliti |
| author_facet | Alessandro Giraudo Cristiano Bolchi Marco Pallavicini Roberto Di Santo Roberta Costi Francesco Saccoliti |
| author_sort | Alessandro Giraudo |
| collection | DOAJ |
| description | <i>Plasmodium</i>, <i>Leishmania</i>, and <i>Trypanosoma</i> 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’s 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’ 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. |
| format | Article |
| id | doaj-art-5e012cb0814d494b905c784e49bb59ae |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj-art-5e012cb0814d494b905c784e49bb59ae2025-01-24T13:45:04ZengMDPI AGPharmaceuticals1424-82472024-12-011812810.3390/ph18010028Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling StrategyAlessandro Giraudo0Cristiano Bolchi1Marco Pallavicini2Roberto Di Santo3Roberta Costi4Francesco Saccoliti5Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, ItalyDipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, I-20133 Milano, ItalyDipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome, ItalyDipartimento di Chimica e Tecnologie del Farmaco, Istituto Pasteur-Fondazione Cenci Bolognetti, “Sapienza” Università di Roma, p.le Aldo Moro 5, I-00185 Rome, ItalyDipartimento di Scienze della Vita, della Salute e delle Professioni Sanitarie, Università degli Studi “Link Campus University”, Via del Casale di S. Pio V 44, I-00165 Rome, Italy<i>Plasmodium</i>, <i>Leishmania</i>, and <i>Trypanosoma</i> 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’s 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’ 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.https://www.mdpi.com/1424-8247/18/1/28photoaffinity labelingtarget deconvolutiontarget identificationantiprotozoal agentskinetoplastid diseases<i>Trypanosoma</i> |
| spellingShingle | Alessandro Giraudo Cristiano Bolchi Marco Pallavicini Roberto Di Santo Roberta Costi Francesco Saccoliti Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy Pharmaceuticals photoaffinity labeling target deconvolution target identification antiprotozoal agents kinetoplastid diseases <i>Trypanosoma</i> |
| title | Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy |
| title_full | Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy |
| title_fullStr | Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy |
| title_full_unstemmed | Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy |
| title_short | Uncovering the Mechanism of Action of Antiprotozoal Agents: A Survey on Photoaffinity Labeling Strategy |
| title_sort | uncovering the mechanism of action of antiprotozoal agents a survey on photoaffinity labeling strategy |
| topic | photoaffinity labeling target deconvolution target identification antiprotozoal agents kinetoplastid diseases <i>Trypanosoma</i> |
| url | https://www.mdpi.com/1424-8247/18/1/28 |
| work_keys_str_mv | AT alessandrogiraudo uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy AT cristianobolchi uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy AT marcopallavicini uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy AT robertodisanto uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy AT robertacosti uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy AT francescosaccoliti uncoveringthemechanismofactionofantiprotozoalagentsasurveyonphotoaffinitylabelingstrategy |