{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,23]],"date-time":"2025-12-23T10:26:13Z","timestamp":1766485573504,"version":"build-2065373602"},"reference-count":39,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T00:00:00Z","timestamp":1700784000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Novartis Institute for Tropical Diseases"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Imidazolopiperazine (IPZ), KAF156, a close analogue of GNF179, is a promising antimalarial candidate. IPZ is effective against Plasmodium falciparum and Plasmodium vivax clinical malaria in human with transmission blocking property in animal models and effective against liver stage parasites. Despite these excellent drug efficacy properties, in vitro parasites have shown resistance to IPZ. However, the mechanism of action and resistance of IPZ remained not fully understood. Here, we used transcriptomic analysis to elucidate mode of action of IPZs. We report, in wild-type parasites GNF179 treatment down regulated lipase enzymes, two metabolic pathways: the hydrolysis of Phosphoinositol 4,5-bipohosphate (PIP2) that produce diacyglycerol (DAG) and the cytosolic calcium Ca2+ homeostasis which are known to be essential for P. falciparum survival and proliferation, as well for membrane permeability and protein trafficking. Furthermore, in wild-type parasites, GNF179 repressed expression of Acyl CoA Synthetase, export lipase 1 and esterase enzymes. Thus, in wild-type parasites only, GNF179 treatment affected enzymes leading lipid metabolism, transport, and synthesis. Lastly, our data revealed that IPZs did not perturb known IPZ resistance genes markers pfcarl, pfact, and pfugt regulations, which are all instead possibly involved in the drug resistance that disturb membrane transport targeted by IPZ.<\/jats:p>","DOI":"10.3390\/genes14122124","type":"journal-article","created":{"date-parts":[[2023,11,24]],"date-time":"2023-11-24T10:10:39Z","timestamp":1700820639000},"page":"2124","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Imidazolopiperazine (IPZ)-Induced Differential Transcriptomic Responses on Plasmodium falciparum Wild-Type and IPZ-Resistant Mutant Parasites"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9087-8439","authenticated-orcid":false,"given":"Laurent","family":"Dembele","sequence":"first","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"},{"name":"African Center of Excellence in Bioinformatics (ACE), Bamako P.O. Box 1805, Mali"},{"name":"Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7739-4437","authenticated-orcid":false,"given":"Antoine","family":"Dara","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1537-9087","authenticated-orcid":false,"given":"Mohamed","family":"Maiga","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"},{"name":"African Center of Excellence in Bioinformatics (ACE), Bamako P.O. Box 1805, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fatoumata O.","family":"Maiga","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"},{"name":"African Center of Excellence in Bioinformatics (ACE), Bamako P.O. Box 1805, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Djeneba","family":"Cissoko","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"},{"name":"African Center of Excellence in Bioinformatics (ACE), Bamako P.O. Box 1805, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-2283","authenticated-orcid":false,"given":"Abdoulaye A.","family":"Djimde","sequence":"additional","affiliation":[{"name":"Malaria Research and Training Center, Faculty of Pharmacy, Universit\u00e9 des Sciences, des Techniques et des Technologies de Bamako (USTTB), DEAP Point G, Bamako P.O. Box 1805, Mali"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,24]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2022). World Malaria Report 2022, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1172\/JCI21682","article-title":"Antimalarial drug resistance","volume":"113","author":"White","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1056\/NEJMoa0808859","article-title":"Artemisinin Resistance in Plasmodium falciparum Malaria","volume":"361","author":"Dondorp","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s11908-010-0099-y","article-title":"Drug-Resistant Malaria: The Era of ACT","volume":"12","author":"Lin","year":"2010","journal-title":"Curr. Infect. Dis. 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