Accelerating Antimalarial Drug Discovery with a New High-Throughput Screen for Fast-Killing Compounds

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2024-11-19 DOI:10.1021/acsinfecdis.4c0032810.1021/acsinfecdis.4c00328

Takaya Sakura, Ryuta Ishii, Eri Yoshida, Kiyoshi Kita, Teruhisa Kato and Daniel Ken Inaoka*,

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引用次数: 0

Abstract

The urgent need for rapidly acting compounds in the development of antimalarial drugs underscores the significance of such compounds in overcoming resistance issues and improving patient adherence to antimalarial treatments. The present study introduces a high-throughput screening (HTS) approach using 1536-well plates, employing Plasmodium falciparum lactate dehydrogenase (PfLDH) combined with nitroreductase (NTR) and fluorescent probes to evaluate inhibition of the growth of the asexual blood stage of malaria parasites. This method was adapted to efficiently assess the speed of action profiling (SAP) in a 384-well plate format, streamlining the traditionally time-consuming screening process. By successfully screening numerous compounds, this approach identified fast-killing hits early in the screening process, addressing challenges associated with artemisinin-based combination therapies. The high-throughput SAP method is expected to be of value in continuously monitoring fast-killing properties during structure–activity relationship studies, expediting the identification and development of novel, rapidly acting antimalarial drugs within phenotypic drug discovery campaigns.

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通过新型高通量筛选快速杀伤性化合物加速抗疟药物的发现

在抗疟药物的开发中迫切需要快速起作用的化合物，这强调了这些化合物在克服耐药性问题和提高患者对抗疟治疗的依从性方面的重要性。本研究采用1536孔板高通量筛选（HTS）方法，利用恶性疟原虫乳酸脱氢酶（PfLDH）联合硝基还原酶（NTR）和荧光探针检测对疟原虫无性血期生长的抑制作用。该方法适用于384孔板格式中有效评估动作分析速度（SAP），简化了传统耗时的筛选过程。通过成功筛选多种化合物，这种方法在筛选过程的早期发现了快速杀伤靶点，解决了与基于青蒿素的联合疗法相关的挑战。高通量SAP方法有望在结构-活性关系研究中持续监测快速杀伤特性，加快在表型药物发现运动中识别和开发新的，快速作用的抗疟疾药物。

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来源期刊

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.