Drugs targeting the liver stage offer many advantages over drugs that merely target the blood stage. First, drugs active against the liver stage represent true causally prophylactic agents that can prevent all disease symptoms, including death, associated with malaria. Secondly, it has been established that while wild-caught mosquitoes may harbor thousands of sporozoites, only ?10 sporozoites are transferred in a single bite to the human host. Over the next 2-3 weeks the sporozoite reproduces in the liver to produce 10,000-30,000 descendants before the schizont ruptures and parasites flood into the bloodstream where the absolute parasite burden may increase to ten thousand billion (1013) circulating plasmodia. Clearly it is advantageous to strike at the liver stage where parasite numbers are low, to diminish the likelihood of selecting for a drug resistant mutant and before the infection has a chance to weaken the defenses of the human host. Our primary goal in this project is to develop a drug combination that is active against P. falciparum, causative agent of the most virulent, often fatal form of malaria. The drug combination will act synergistically while targeting the parasite in the liver, blood and also the vector stages that are critical for disease transmission. Studies (by us and others) have shown that ELQ-300 targets all 3 of these life cycle stages. The ultimate objective of our proposed work is the development of an inexpensive ELQ-300 prodrug that can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria and support the worldwide effort to control and eradicate the disease. This study focuses on the combination of ELQ-300 prodrugs with biguanides including proguanil. We seek a better understanding of the biochemical mechanism that underlies the antimalarial synergism that exists between ELQ-300 and biguanides. A better understanding of this interaction will help to design a biguanide/ELQ-300 prodrug combination that is safe for use in humans for weekly prophylaxis and treatment of malaria.
ELQ-300 is a selectively potent inhibitor of the Qi site of Plasmodium falciparum cytochrome bc1 with activity against all life cycle stages of the parasite including liver, blood and vector stages. In this application we focus on the optimization of ELQ-300 prodrugs for enhanced performance in vivo and on the biochemical mechanism underlying the synergism that exists between this class of drugs and biguanides including proguanil.
|Anghel, Nicoleta; Balmer, Vreni; Müller, Joachim et al. (2018) Endochin-Like Quinolones Exhibit Promising Efficacy Against Neospora Caninum in vitro and in Experimentally Infected Pregnant Mice. Front Vet Sci 5:285|
|Alday, P Holland; Bruzual, Igor; Nilsen, Aaron et al. (2017) Genetic Evidence for Cytochrome b Qi Site Inhibition by 4(1H)-Quinolone-3-Diarylethers and Antimycin in Toxoplasma gondii. Antimicrob Agents Chemother 61:|
|Frueh, Lisa; Li, Yuexin; Mather, Michael W et al. (2017) Alkoxycarbonate Ester Prodrugs of Preclinical Drug Candidate ELQ-300 for Prophylaxis and Treatment of Malaria. ACS Infect Dis 3:728-735|
|Stickles, Allison M; Smilkstein, Martin J; Morrisey, Joanne M et al. (2016) Atovaquone and ELQ-300 Combination Therapy as a Novel Dual-Site Cytochrome bc1 Inhibition Strategy for Malaria. Antimicrob Agents Chemother 60:4853-9|
|Ortiz, Diana; Forquer, Isaac; Boitz, Jan et al. (2016) Targeting the Cytochrome bc1 Complex of Leishmania Parasites for Discovery of Novel Drugs. Antimicrob Agents Chemother 60:4972-82|
|Lawres, Lauren A; Garg, Aprajita; Kumar, Vidya et al. (2016) Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone. J Exp Med 213:1307-18|
|Miley, Galen P; Pou, Sovitj; Winter, Rolf et al. (2015) ELQ-300 prodrugs for enhanced delivery and single-dose cure of malaria. Antimicrob Agents Chemother 59:5555-60|
|Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M et al. (2015) Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy. Am J Trop Med Hyg 92:1195-201|
|Stickles, Allison M; de Almeida, Mariana Justino; Morrisey, Joanne M et al. (2015) Subtle changes in endochin-like quinolone structure alter the site of inhibition within the cytochrome bc1 complex of Plasmodium falciparum. Antimicrob Agents Chemother 59:1977-82|
|Janowsky, Aaron; Eshleman, Amy J; Johnson, Robert A et al. (2014) Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. Psychopharmacology (Berl) 231:2771-83|
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