Drug Interaction Studies of Cabamiquine:Ganaplacide Combination against Hepatic Plasmodium berghei.

IF 4 2区 医学 Q2 CHEMISTRY, MEDICINAL
ACS Infectious Diseases Pub Date : 2025-01-10 Epub Date: 2024-12-10 DOI:10.1021/acsinfecdis.4c00563
Isabella Ramella Gal, Claudia Demarta-Gatsi, Diana Fontinha, Francisca Arez, Sebastian G Wicha, Matthias Rottmann, Helena Nunes-Cabaço, Johanne Blais, Jay Prakash Jain, Suresh B Lakshminarayana, Catarina Brito, Miguel Prudêncio, Paula M Alves, Thomas Spangenberg
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引用次数: 0

Abstract

New antimalarial combination therapies with novel modes of action are required to counter the emergence and spread of Plasmodium drug resistance against existing therapeutics. Here, we present a study to evaluate the preventive activity of a combination of clinical antimalarial drug candidates, cabamiquine and ganaplacide, that have multistage activity against the liver and blood stages of Plasmodium infection. Cabamiquine (DDD107498, M5717) inhibits parasite protein synthesis, and ganaplacide (KAF156) inhibits protein trafficking, blocks the establishment of new permeation pathways, and causes endoplasmic reticulum expansion. The pharmacodynamic parameters of a combination of the two compounds were assessed employing a pharmacometrics approach in conjunction with in vitro-in silico checkerboard analysis. The in vitro study was performed on a previously established 3D infection platform based on human hepatic cell lines that sustain infection by rodent P. berghei parasites. The in vivo efficacy of this drug combination was assessed against the liver stage of the P. berghei. Our results show that the combination of both drugs at the tested concentrations does not interfere with the drugs respective mode of action or affect hepatocyte cell viability. The drug combination was fully effective in preventing the appearance of blood stage parasites when a systemic plasma Cav0-24/EC50 ratio >2 for ganaplacide and >5 for cabamiquine was achieved. These findings demonstrate that chemoprevention using a combination of cabamiquine and ganaplacide has the potential to target the asymptomatic liver stage of Plasmodium infection and prevent the development of parasitemia.

卡巴喹-加那普胺联合抗肝伯氏疟原虫药物相互作用研究。
需要具有新作用方式的新型抗疟联合疗法来对抗疟原虫对现有疗法的耐药性的出现和传播。在这里,我们提出了一项研究,以评估临床抗疟候选药物卡巴喹和加那普胺的联合预防活性,这两种药物对肝脏和血液阶段的疟原虫感染具有多阶段的活性。Cabamiquine (DDD107498, M5717)抑制寄生虫蛋白合成,ganaplacide (KAF156)抑制蛋白质运输,阻断新的渗透途径的建立,导致内质网扩张。采用药物计量学方法结合体外硅棋盘分析评估了两种化合物组合的药效学参数。体外研究是在先前建立的基于人肝细胞系的3D感染平台上进行的,该细胞系可承受啮齿动物伯氏疟原虫的感染。该药物组合的体内疗效是针对伯氏单胞菌的肝期进行评估的。我们的研究结果表明,两种药物在测试浓度下的组合不会干扰药物各自的作用模式或影响肝细胞的活力。当加那普胺和卡巴米喹达到全身血浆Cav0-24/EC50比值> -2和> - 5时,联合用药可完全有效地预防血期寄生虫的出现。这些发现表明,联合使用卡巴喹和加那普胺的化学预防有可能针对疟原虫感染的无症状肝期,并预防寄生虫病的发展。
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来源期刊
ACS Infectious Diseases
ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES
CiteScore
9.70
自引率
3.80%
发文量
213
期刊介绍: ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.
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