Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening.
Safe drugs with high potential to block malaria transmission revealed by a spleen-mimetic screening.
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DOI：
10.1038/s41467-023-37359-2
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发表时间：
2023-04-07
影响因子：
16.6
通讯作者：
Buffet, Pierre
中科院分区：
文献类型：
--
作者：
Carucci, Mario;Duez, Julien;Tarning, Joel;Garcia-Barbazan, Irene;Fricot-Monsinjon, Aurelie;Sissoko, Abdoulaye;Dumas, Lucie;Gamallo, Pablo;Beher, Babette;Amireault, Pascal;Dussiot, Michael;Dao, Ming;Hull, Mitchell V.;McNamara, Case W.;Roussel, Camille;Ndour, Papa Alioune;Sanz, Laura Maria;Gamo, Francisco Javier;Buffet, Pierre
疟疾寄生虫如恶性疟原虫在红细胞（RBC）中繁殖，当它们的变形能力改变时，红细胞被脾脏从血液中清除。因此，药物诱导的恶性疟原虫感染的红细胞硬化应诱导其从血流中消除。在这里，基于这种原始的机械方法，我们确定了具有强大潜力的安全药物来阻断疟疾传播。通过用拟脾微滤器筛选13555种化合物，我们鉴定了82种靶向恶性疟原虫循环传播形式的化合物。NITD 609是一种口服PfATPase抑制剂，对恶性疟原虫具有已知的作用，在纳摩尔浓度下体外杀死并加强了传播阶段。短期暴露于TD-6450（一种口服NS 5A丙型肝炎病毒抑制剂），在高纳摩尔浓度下，可使传播寄生虫阶段变硬，并在体外杀死无性阶段。一项具有主要安全性结局和次要药代动力学结局的人体I期研究（https：clinicaltrials.gov，ID：NCT 02022306）显示，单次或多次给药均未发生重度不良事件。药代动力学建模显示，接受短期TD-6450治疗的受试者血浆中可达到这些浓度。这一与生理学相关的筛选确定了多种作用机制，并确定了具有很大潜力的安全药物作为疟疾传播阻断剂，可在临床试验中迅速进行测试。作者提出了他们的脾模拟过滤方法，微过滤，并利用这种方法在药物筛选，以确定化合物，诱导对恶性疟原虫感染的红细胞的硬化作用。他们在I期临床试验中评估了一种已鉴定化合物的安全性和耐受性。
Malaria parasites like Plasmodium falciparum multiply in red blood cells (RBC), which are cleared from the bloodstream by the spleen when their deformability is altered. Drug-induced stiffening of Plasmodium falciparum-infected RBC should therefore induce their elimination from the bloodstream. Here, based on this original mechanical approach, we identify safe drugs with strong potential to block the malaria transmission. By screening 13 555 compounds with spleen-mimetic microfilters, we identified 82 that target circulating transmissible form of P. falciparum. NITD609, an orally administered PfATPase inhibitor with known effects on P. falciparum, killed and stiffened transmission stages in vitro at nanomolar concentrations. Short exposures to TD-6450, an orally-administered NS5A hepatitis C virus inhibitor, stiffened transmission parasite stages and killed asexual stages in vitro at high nanomolar concentrations. A Phase 1 study in humans with a primary safety outcome and a secondary pharmacokinetics outcome (https://clinicaltrials.gov, ID: NCT02022306) showed no severe adverse events either with single or multiple doses. Pharmacokinetic modelling showed that these concentrations can be reached in the plasma of subjects receiving short courses of TD-6450. This physiologically relevant screen identified multiple mechanisms of action, and safe drugs with strong potential as malaria transmission-blocking agents which could be rapidly tested in clinical trials. Authors propose their splenic mimetic filtration method, microsphiltration, and utilise this approach in a drug-screen, to identify compounds that induce a stiffening effect on Plasmodium falciparum-infected erythrocytes. They proceed to assess safety and tolerability of one identified compound in a phase I clinical trial.
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影响因子：
3.7
作者：
Coulibaly B;Zoungrana A;Mockenhaupt FP;Schirmer RH;Klose C;Mansmann U;Meissner PE;Müller O
通讯作者：
Müller O
影响因子：
4.6
作者：
Dennis ASM;Rosling JEO;Lehane AM;Kirk K
通讯作者：
Kirk K
DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
影响因子：
5.2
作者：
D'Alessandro, Sarah;Silvestrini, Francesco;Taramelli, Donatella
通讯作者：
Taramelli, Donatella
影响因子：
14.8
作者：
Duez, Julien;Carucci, Mario;Buffet, Pierre
通讯作者：
Buffet, Pierre