{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:47:15Z","timestamp":1787028435286,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T00:00:00Z","timestamp":1600819200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007359","name":"Fondazione Banco di Sardegna","doi-asserted-by":"publisher","award":["Prot. U1056.2014\/AI.938MGB Prat. 2014.0040"],"award-info":[{"award-number":["Prot. U1056.2014\/AI.938MGB Prat. 2014.0040"]}],"id":[{"id":"10.13039\/100007359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Resistance to antimalarial drugs has spread rapidly over the past few decades. The WHO recommends artemisinin-based combination therapies for the treatment of uncomplicated malaria, but unfortunately these approaches are losing their efficacy in large areas of Southeast Asia. In 2016, artemisinin resistance was confirmed in 5 countries of the Greater Mekong subregion. We focused our study on Syk inhibitors as antimalarial drugs. The Syk protein is present in human erythrocytes, and the membrane of protein band 3 is its major target following activation by oxidant stress. Tyr phosphorylation of band 3 occurs during P. falciparum growth, leading to the release of microparticles containing hemicromes and structural weakening of the host cell membrane, simplifying merozoite reinfection. Syk inhibitors block these events by interacting with the Syk protein\u2019s catalytic site. We performed in vitro proteomics and in silico studies and compared the results. In vitro studies were based on treatment of the parasite\u2019s cellular cultures with different concentrations of Syk inhibitors, while proteomics studies were focused on the Tyr phosphorylation of band 3 by Syk protein with the same concentrations of drugs. In silico studies were based on different molecular modeling approaches in order to analyze and optimize the ligand\u2013protein interactions and obtain the highest efficacy in vitro. In the presence of Syk inhibitors, we observed a marked decrease of band 3 Tyr phosphorylation according to the increase of the drug\u2019s concentration. Our studies could be useful for the structural optimization of these compounds and for the design of novel Syk inhibitors in the future.<\/jats:p>","DOI":"10.3390\/ijms21197009","type":"journal-article","created":{"date-parts":[[2020,9,23]],"date-time":"2020-09-23T09:28:08Z","timestamp":1600853288000},"page":"7009","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Syk Inhibitors: New Computational Insights into Their Intraerythrocytic Action in Plasmodium falciparum Malaria"],"prefix":"10.3390","volume":"21","author":[{"given":"Giuseppe","family":"Marchetti","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8258-7332","authenticated-orcid":false,"given":"Alessandro","family":"Dess\u00ec","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Biomolecular Chemistry, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4626-4792","authenticated-orcid":false,"given":"Roberto","family":"Dallocchio","sequence":"additional","affiliation":[{"name":"National Research Council (CNR) Institute of Biomolecular Chemistry, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1439-3920","authenticated-orcid":false,"given":"Ioannis","family":"Tsamesidis","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"},{"name":"UMR 152 Pharma-Dev, Universit\u00e9 de Toulouse III, IRD, UPS, 31000 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Carmina","family":"Pau","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco Michelangelo","family":"Turrini","sequence":"additional","affiliation":[{"name":"Department of Oncology, University of Turin, 10126 Turin, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2954-7053","authenticated-orcid":false,"given":"Antonella","family":"Pantaleo","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.it.2005.02.002","article-title":"Src and Syk kinases: Key regulators of phagocytic cell activation","volume":"26","author":"Berton","year":"2005","journal-title":"Trends Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1093\/oxfordjournals.jbchem.a002970","article-title":"Structure and function of Syk protein-tyrosine kinase","volume":"130","author":"Sada","year":"2001","journal-title":"J. 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