免疫及传染病学系Flaminia Catteruccia研究团队取得一项新突破。他们报道了蚊媒疟疾防治中疟原虫靶点的体内筛选。该研究于2025年5月21日发表于国际一流学术期刊《自然》杂志上。

课题组人员进行了体内筛选化合物对抗恶性疟原虫的蚊子阶段的发展。在测试的81种化合物中，有28种不同的作用模式，其中22种对蚊子中肠腔的早期寄生虫有活性，从而防止了感染的建立。然后以药物化学为主题，提高屏幕上最热门药物的抗寄生虫活性。研究人员制备了几种抑制P恶性疟原虫细胞色素bc₁复合物（CytB）。两种靶向CytB中不同位点的先导化合物（Q_o和Q_i）在掺入和/或挤压成蚊帐状聚乙烯薄膜时显示出有效、持久和稳定的活性。在抗杀虫剂的蚊子中，ELQ活性完全保留，并且对这些化合物有抗性的寄生虫在蚊子阶段发育受损。这些数据表明，将ELQ化合物纳入LLINs以抵消杀虫剂耐药性和减少疟疾传播是有希望的。

据了解，由于若干因素，包括媒介按蚊对长效驱虫蚊帐（LLINs）中所使用的杀虫剂的广泛耐药性，疟疾死亡人数的下降最近已停止。减轻杀虫剂抗性的一种方法是在蚊子发育阶段通过将抗寄生虫化合物掺入LLINs直接杀死寄生虫。这种策略可以防止寄生虫继续传播，即使杀虫剂失去效力。

附：英文原文

Title: In vivo screen of Plasmodium targets for mosquito-based malaria control

Author: Probst, Alexandra S., Paton, Douglas G., Appetecchia, Federico, Bopp, Selina, Adams, Kelsey L., Rinvee, Tasneem A., Pou, Sovitj, Winter, Rolf, Du, Esrah W., Yahiya, Sabrina, Vidoudez, Charles, Singh, Naresh, Rodrigues, Janneth, Castaeda-Casado, Pablo, Tammaro, Chiara, Chen, Daisy, Godinez-Macias, Karla P., Jaramillo, Jasmine L., Poce, Giovanna, Rubal, Michael J., Nilsen, Aaron, Winzeler, Elizabeth A., Baum, Jake, Burrows, Jeremy N., Riscoe, Michael K., Wirth, Dyann F., Catteruccia, Flaminia

Issue&Volume: 2025-05-21

Abstract: The decline in malaria deaths has recently stalled owing to several factors, including the widespread resistance of Anopheles vectors to the insecticides used in long-lasting insecticide-treated nets (LLINs)1,2. One way to mitigate insecticide resistance is to directly kill parasites during their mosquito-stage of development by incorporating antiparasitic compounds into LLINs. This strategy can prevent onward parasite transmission even when insecticides lose efficacy3,4. Here, we performed an in vivo screen of compounds against the mosquito stages of Plasmodium falciparum development. Of the 81 compounds tested, which spanned 28 distinct modes of action, 22 were active against early parasite stages in the mosquito midgut lumen, which in turn prevented establishment of infection. Medicinal chemistry was then used to improve antiparasitic activity of the top hits from the screen. We generated several endochin-like quinolones (ELQs) that inhibited the P.falciparum cytochrome bc1 complex (CytB). Two lead compounds that targeted separate sites in CytB (Qo and Qi) showed potent, long-lasting and stable activity when incorporated and/or extruded into bed net-like polyethylene films. ELQ activity was fully preserved in insecticide-resistant mosquitoes, and parasites resistant to these compounds had impaired development at the mosquito stage. These data demonstrate the promise of incorporating ELQ compounds into LLINs to counteract insecticide resistance and to reduce malaria transmission.

DOI: 10.1038/s41586-025-09039-2

Source: https://www.nature.com/articles/s41586-025-09039-2