作者: Botté, Cyrille ; Riscoe, Michael K ; Ouji, Manel ; Nguyen, Michel ; Benoit-Vical, Françoise ; Rengel, David ; Reyser, Thibaud ; Augereau, Jean-Michel ; Dutreuil, Axelle ; Marcellin, Marlène ; Yamaryo-Botté, Yoshiki ; Paloque, Lucie ; Burlet-Schiltz, Odile ; Riscoe, Michael K.

Emergence and spread of parasite resistance to artemisinins, the first-line antimalarial therapy, threaten the malaria eradication policy. To identify therapeutic targets to eliminate artemisinin-resistant parasites, the functioning of the apicoplast and the mitochondrion was studied, focusing on the fatty acid synthesis type II (FASII) pathway in the apicoplast and the electron transfer chain in the mitochondrion. A significant enrichment of the FASII pathway among the up-regulated genes in artemisinin-resistant parasites under dihydroartemisinin treatment was found, in agreement with published transcriptomic data. However, using GC-MS analyzes of fatty acids, we demonstrated for the first time that the FASII pathway is non-functional, ruling out the use of FASII inhibitors to target artemisinin-resistant parasites. Conversely, by assessing the modulation of the oxygen consumption rate, we evidenced that mitochondrial respiration remains functional and flexible in artemisinin-resistant parasites and even at the quiescent stage. Two novel compounds targeting electron transport chain (ELQ300, ELQ400) efficiently killed quiescent artemisinin-resistant parasites. Therefore, mitochondrial respiration represents a key target for the elimination of artemisinin-resistant persistent Plasmodium falciparum parasites.

2024-07-12·ACS Infectious Diseases

3-Position Biaryl Endochin-like Quinolones with Enhanced Antimalarial Performance

Article

作者: Handford, Mason J ; Riscoe, Teresa M ; Kelly, Jane X ; Aleshnick, Maya ; Vaidya, Akhil B ; Pou, Sovitj ; Doggett, J Stone ; Nepal, Binod ; Liebman, Katherine ; Smilkstein, Martin J ; Li, Yuexin ; Mather, Michael W ; Nilsen, Aaron ; Kirtley, Payton J ; Dodean, Rozalia A ; Winter, Rolf W ; Zakharov, Lev N ; Kortagere, Sandhya ; Riscoe, Michael K ; Wilder, Brandon K ; Alday, P Holland ; Laxson, Sydney

ELQ-300 is a potent antimalarial drug with activity against blood, liver, and vector stages of the disease. A prodrug, ELQ-331, exhibits reduced crystallinity and improved in vivo efficacy in preclinical testing, and currently, it is in the developmental pipeline for once-a-week dosing for oral prophylaxis against malaria. Because of the high cost of developing a new drug for human use and the high risk of drug failure, it is prudent to have a back-up plan in place. Here we describe ELQ-596, a member of a new subseries of 3-biaryl-ELQs, with enhanced potency in vitro against multidrug-resistant Plasmodium falciparum parasites. ELQ-598, a prodrug of ELQ-596 with diminished crystallinity, is more effective vs murine malaria than its progenitor ELQ-331 by 4- to 10-fold, suggesting that correspondingly lower doses could be used to protect and cure humans of malaria. With a longer bloodstream half-life in mice compared to its progenitor, ELQ-596 highlights a novel series of next-generation ELQs with the potential for once-monthly dosing for protection against malaria infection. Advances in the preparation of 3-biaryl-ELQs are presented along with preliminary results from experiments to explore key structure-activity relationships for drug potency, selectivity, pharmacokinetics, and safety.

2024-07-01·European Journal of Pharmaceutical Sciences

Long-acting intramuscular injections of ELQ-331, an antimalarial agent

Article

作者: Dodean, Rozalia A ; Nilsen, Aaron ; Chen, Jiaming ; Shankar, Gita ; Winter, Rolf W ; Riscoe, Michael K ; Karunakaran, Dipu ; Smilkstein, Martin J ; Pham, Kim Hue Nicky ; Mutyam, Shravan K ; Fu, Melody ; Pou, Sovitj

The overarching premise of this investigation is that injectable, long-acting antimalarial medication would encourage adherence to a dosage regimen for populations at risk of contracting the disease. To advance support for this goal, we have developed oil-based formulations of ELQ-331 (a prodrug of ELQ-300) that perform as long-acting, injectable chemoprophylactics with drug loading as high as 160 mg/ml of ELQ-331. In a pharmacokinetic study performed with rats, a single intramuscular injection of 12.14 mg/kg maintained higher plasma levels than the previously established minimum fully protective plasma concentration (33.25 ng/ml) of ELQ-300 for more than 4 weeks. The formulations were well tolerated by the rats and the tested dose produced no adverse reactions. We believe that by extending the length of time between subsequent injections, these injectable oil-based solutions of ELQ-331 can offer a more accessible, low-cost option for long-acting disease prevention and reduced transmission in malaria-endemic regions and may also be of use to travelers.

100 项与 ELQ-300 相关的药物交易

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