Ochora Douglas O, Mogire Reagan M, Masai Rael J, Yeda Redemptah A, Mwakio Edwin W, Amwoma Joseph G, Wakoli Dancan M, Yenesew Abiy, Akala Hoseah M
Department of Biological Sciences, School of Pure and Applied Sciences, Kisii University, P.O. Box 408-40200, Kisii, Kenya.
DSI/NWU, Preclinical Drug Development Platform, Faculty of Health Sciences, North-West University, Private Bag X6001, 2520, Potchefstroom, South Africa.
Heliyon. 2023 Aug 1;9(8):e18863. doi: 10.1016/j.heliyon.2023.e18863. eCollection 2023 Aug.
High malaria mortality coupled with increased emergence of resistant multi-drug resistant strains of parasite, warrants the development of new and effective antimalarial drugs. However, drug design and discovery are costly and time-consuming with many active antimalarial compounds failing to get approved due to safety reasons. To address these challenges, the current study aimed at testing the antiplasmodial activities of approved drugs that were predicted using a target-similarity approach. This approach is based on the fact that if an approved drug used to treat another disease targets a protein similar to protein, then the drug will have a comparable effect on . In a previous study, antiplasmodial activities of 10 approved drugs was reported of the total 28 approved drugs In this study, six out of 18 drugs that were previously not tested, namely epirubicin, irinotecan, venlafaxine, palbociclib, pelitinib, and PD153035 were tested for antiplasmodial activity. The drug susceptibility assays against five reference strains (D6, 3D7, W2, DD2, and F32 ART) and assays against fresh clinical isolates were done using the malaria SYBR Green I assay. Standard antimalarial drugs were included as controls. Epirubicin and irinotecan showed excellent antiplasmodial activity against field isolates with mean IC values of 0.044 ± 0.033 μM and 0.085 ± 0.055 μM, respectively. Similar activity was observed against W2 strain where epirubicin had an IC value of 0.004 ± 0.0009 μM, palbociclib 0.056 ± 0.006 μM, and pelinitib 0.057 ± 0.013 μM For the DD2 strain, epirubicin, irinotecan and PD 153035 displayed potent antiplasmodial activity (IC < 1 μM). Epirubicin and irinotecan showed potent antiplasmodial activities (IC < 1 μM) against DD2, D6, 3D7, and F32 ART strains and field isolates This shows the potential use of these drugs as antimalarials. All the tested drugs showed antiplasmodial activities with IC values below 20 μM, which suggests that our target similarity-based strategy is successful at predicting antiplasmodial activity of compounds thereby circumventing challenges in antimalarial drug discovery.
疟疾死亡率高，加上寄生虫多药耐药菌株的出现日益增加，这就需要研发新的有效抗疟药物。然而，药物设计和发现成本高昂且耗时，许多有活性的抗疟化合物由于安全原因未能获批。为应对这些挑战，本研究旨在测试使用靶点相似性方法预测的已获批药物的抗疟原虫活性。这种方法基于这样一个事实：如果一种用于治疗另一种疾病的已获批药物靶向一种与[蛋白质名称]相似的蛋白质，那么该药物对[蛋白质名称]将有类似的效果。在之前的一项研究中，报告了28种已获批药物中的10种药物的抗疟原虫活性。在本研究中，对之前未测试的18种药物中的6种，即表柔比星、伊立替康、文拉法辛、帕博西尼、培利替尼和PD153035进行了抗疟原虫活性测试。使用疟疾SYBR Green I检测法对5种参考菌株（D6、3D7、W2、DD2和F32 ART）进行药物敏感性检测，并对新鲜临床分离株进行检测。纳入标准抗疟药物作为对照。表柔比星和伊立替康对野外分离株显示出优异的抗疟原虫活性，平均IC值分别为0.044±0.033μM和0.085±0.055μM。在针对W2菌株的检测中也观察到类似活性，表柔比星的IC值为0.004±0.0009μM，帕博西尼为0.056±0.006μM，培利替尼为0.057±0.013μM。对于DD2菌株，表柔比星、伊立替康和PD 153035显示出强效抗疟原虫活性（IC<1μM）。表柔比星和伊立替康对DD2、D6、3D7和F32 ART菌株以及野外分离株显示出强效抗疟原虫活性（IC<1μM）。这表明这些药物作为抗疟药具有潜在用途。所有测试药物均显示出IC值低于20μM的抗疟原虫活性，这表明我们基于靶点相似性的策略成功地预测了化合物的抗疟原虫活性，从而规避了抗疟药物发现中的挑战。
