Stepwise in vitro screening of MMV pathogen box compounds against Plasmodium falciparum to identify potent antimalarial candidates

IF 4.1 2区医学 Q1 PARASITOLOGY

International Journal for Parasitology: Drugs and Drug Resistance Pub Date : 2023-08-01 DOI:10.1016/j.ijpddr.2023.05.005

Haddijatou Mbye , Fatoumata Bojang , Fatou Kene Jaiteh , Aminata Jawara , Bekai Njie , Simon Correa , Umberto D'Alessandro , Alfred Amambua-Ngwa

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引用次数: 1

Abstract

Development of resistance to deployed antimalarial drugs is inevitable and needs prompt and continuous discovery of novel candidate drugs. Therefore, the antimalarial activity of 125 compounds from the Medicine for Malaria Ventures (MMV) pathogen box was determined. Combining standard IC₅₀ and normalised growth rate inhibition (GR₅₀) analyses, we found 16 and 22 compounds had higher potencies than CQ respectively. Seven compounds with relatively high potencies (low GR₅₀ and IC₅₀) against P. falciparum 3D7 were further analysed. Three of these were tested on 10 natural P. falciparum isolates from The Gambia using our newly developed parasite survival rate assay (PSRA).

According to the IC₅₀, GR₅₀ and PSRA analyses, compound MMV667494 was most potent and highly cytotoxic to parasites. MMV010576 was slow acting but more potent than dihydroartemisinin (DHA) 72 h after exposure. MMV634140 was potent against the laboratory-adapted 3D7 isolate, but 4 out of 10 natural Gambian isolates survived and replicated slowly despite 72 h of exposure to the compound, suggesting potential drug tolerance and risk of resistance development.

These results emphasise the usefulness of in vitro testing as a starting point for drug discovery. Improved approaches to data analyses and the use of natural isolates will facilitate the prioritisation of compounds for further clinical development.

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逐步筛选抗恶性疟原虫的MMV病原菌盒化合物，以确定有效的抗疟候选药物

对已部署的抗疟药物产生耐药性是不可避免的，需要迅速和持续地发现新的候选药物。因此，测定了来自疟疾风险医学（MMV）病原体盒的125种化合物的抗疟活性。结合标准IC50和归一化生长速率抑制（GR50）分析，我们发现16种和22种化合物分别比CQ具有更高的效力。进一步分析了对恶性疟原虫3D7具有相对较高效力（低GR50和IC50）的七种化合物。其中三种使用我们新开发的寄生虫存活率测定法（PSRA）在冈比亚的10个天然恶性疟原虫分离株上进行了测试。根据IC50、GR50和PSRA分析，化合物MMV667494对寄生虫最有效且具有高度细胞毒性。MMV010576作用缓慢，但在暴露72小时后比双氢青蒿素（DHA）更有效。MMV634140对实验室适应的3D7分离株有效，但10个冈比亚天然分离株中有4个存活下来，尽管暴露于该化合物72小时，但复制缓慢，这表明存在潜在的耐药性和耐药性发展风险。这些结果强调了体外测试作为药物发现起点的有用性。数据分析方法的改进和天然分离物的使用将有助于化合物的优先顺序，以供进一步的临床开发。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

International Journal for Parasitology: Drugs and Drug Resistance PARASITOLOGY-PHARMACOLOGY & PHARMACY

CiteScore

7.90

自引率

7.50%

发文量

审稿时长

48 days

期刊介绍： The International Journal for Parasitology – Drugs and Drug Resistance is one of a series of specialist, open access journals launched by the International Journal for Parasitology. It publishes the results of original research in the area of anti-parasite drug identification, development and evaluation, and parasite drug resistance. The journal also covers research into natural products as anti-parasitic agents, and bioactive parasite products. Studies can be aimed at unicellular or multicellular parasites of human or veterinary importance.