Malaria parasite transmission cycles require an obligatory developmental stage in the Anopheles mosquito vector. In the era of global malaria elimination and eradication, there is emergent emphasis on the development of interventions that break the transmission cycle. While there are several existing antimalarials that have been shown to be effective in blocking the parasite’s jump from humans to mosquitoes, to prevent parasite breakthrough resulting from overlapping resistance mechanisms, new pathways that can be targeted by small molecules (and eventually drugs) need to be identified. We used four natural product compounds, two usnic acid derivatives as well as parthenin and parthenolide as chemical probes to explore and identify drug-susceptible pathways during gametocyte-to-ookinete transition. We measured efficacy by a battery of quantitative, functional approaches including high-content fluorescence image capture, imaging flow cytometry and standard membrane feeding assay (SMFA). Two usnic acid (UA) derivatives, BT-122 and BT-37 were extremely potent in blocking P. falciparum and P. berghei zygote-to-ookinete maturation in vivo and in vitro. We further modified BT-37 with a UV-crosslinking probe and identified its putative targets in zygotes by mass spectrometry. We also observed that parthenin appeared to be more effective in blocking gamete-to-zygote formation than parthenolide; although the latter compound has a more promising pharmacological profile based on Phase I clinical trials. Importantly, we noted that exposure of day 15 stage V gametocytes to parthenin (1 µg/ml) for 24 hours, followed by drug wash out and incubation in parthenin-free culture medium for another 24 hours resulted in the complete blockade of mosquito infection as measured by SMFA. Chemical derivitizations of parthenin are being explored to develop a new crosslinking probe to permit subsequent identification of its candidate target molecules in Plasmodium stage V gametocytes. We envision that these studies will illuminate the potential mechanism of action that results in the inactivation of this important transmission stage.
|Titolo:||Chemical probe platforms identify targetable molecules and pathways that are involved in Plasmodium gametocyte-to-ookinete transition in the mosquito|
VEROTTA, LUISELLA (Penultimo)
|Data di pubblicazione:||25-ott-2015|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
Settore BIO/10 - Biochimica
|Citazione:||Chemical probe platforms identify targetable molecules and pathways that are involved in Plasmodium gametocyte-to-ookinete transition in the mosquito / R. Pastrana-Mena , D.K. Mathias, J. Balaich, D. Tao, M. Delves, R. Yee, K. Rajaram, B. Jackson, J.G. King, B. Torto, B. Trucchi, W. Foster, L. Verotta, R.R. Dinglasan. ((Intervento presentato al 64. convegno American Society of Tropical medicine & Hygiene (ASTMH) Annual Meeting tenutosi a Philadelphia nel 2015.|
|Appare nelle tipologie:||14 - Intervento a convegno non pubblicato|