Instituto Rene Rachou, FIOCRUZ-MG, Belo Horizonte, Minas Gerais, Brazil.
Laboratório de Entomologia, FIOCRUZ-RO, Porto Velho, Rondônia, Brazil.
Int J Parasitol Drugs Drug Resist. 2021 Dec;17:150-155. doi: 10.1016/j.ijpddr.2021.09.003. Epub 2021 Sep 22.
Human malaria continues to be a public health problem and an important cause of morbidity and mortality in the world. Malaria control is achieved through both individual protection against mosquito bites and drug treatment, which is hampered by the spread of Plasmodium falciparum resistance to most antimalarials, including artemisinin derivatives. One of the key pharmacological strategies for controlling malaria is to block transmission of the parasites to their mosquito vectors. Following this rational, MEFAS, a synthetic hybrid salt derived from artesunate (AS) and mefloquine has been previously reported for its activity against asexual P. falciparum parasites in vitro, in addition to a pronounced reduction in the viability of mature gametocytes. Herein, MEFAS was tested against asexual forms of Plasmodium vivax and for its ability to block malaria transmission in Anopheles darlingi mosquitoes in a membrane feeding assay using P. vivax field isolates. MEFAS demonstrated high potency, with a IC50 of 6.5 nM against asexual forms of P. vivax. At 50 μM, MEFAS completely blocked oocyst formation in mosquitoes, regardless of the oocyst number in the control group. At lower doses, MEFAS reduced oocyst prevalence by greater than 20%. At equivalent doses, AS irregularly reduced oocyst formation and caused only slight inhibition of mosquito infections. These results highlight the potential of MEFAS as a novel transmission-blocking molecule, as well as its high blood schizonticidal activity against P. vivax and P. falciparum field isolates, representing a starting point for further development of a new drug with dual antimalarial activity.
人类疟疾仍然是一个公共卫生问题，也是世界上发病率和死亡率的重要原因。疟疾的控制是通过个人防止蚊子叮咬和药物治疗来实现的，但这受到疟原虫对大多数抗疟药物（包括青蒿素衍生物）的耐药性传播的阻碍。控制疟疾的一个关键药理学策略是阻止寄生虫传播给它们的蚊子媒介。基于这一合理的原理，我们之前报道了 MEFAS，这是一种源自青蒿琥酯（AS）和甲氟喹的合成混合盐，对体外无性疟原虫寄生虫具有活性，此外还显著降低成熟配子体的活力。在此，我们在膜喂养试验中用疟原虫 vivax 现场分离株测试了 MEFAS 对无性疟原虫 vivax 的作用及其阻断致倦库蚊传播疟疾的能力。MEFAS 表现出高活性，对无性疟原虫 vivax 的 IC50 为 6.5 nM。在 50 μM 时，MEFAS 完全阻止了卵囊的形成，无论对照组中的卵囊数量如何。在较低剂量下，MEFAS 将卵囊的流行率降低了 20%以上。在等效剂量下，AS 不规则地减少了卵囊的形成，并且仅对蚊子感染产生轻微的抑制作用。这些结果突出了 MEFAS 作为一种新型的阻断传播分子的潜力，以及它对疟原虫 vivax 和疟原虫 falciparum 现场分离株的高血液裂殖体活性，为进一步开发具有双重抗疟活性的新药提供了起点。
