Varghese Swapna, Rahmani Raphaël, Drew Damien R, Beeson James G, Baum Jake, Smith Brian J, Baell Jonathan B
La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia.
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia.
ChemMedChem. 2021 Feb 17;16(4):679-693. doi: 10.1002/cmdc.202000399. Epub 2020 Nov 10.
Malarial parasites employ actin dynamics for motility, and any disruption to these dynamics renders the parasites unable to effectively establish infection. Therefore, actin presents a potential target for malarial drug discovery, and naturally occurring actin inhibitors such as latrunculins are a promising starting point. However, the limited availability of the natural product and the laborious route for synthesis of latrunculins have hindered their potential development as drug candidates. In this regard, we recently described novel truncated latrunculins, with superior actin binding potency and selectivity towards P. falciparum actin than the canonical latrunculin B. In this paper, we further explore the truncated latrunculin core to summarize the SAR for inhibition of malaria motility. This study helps further understand the binding pattern of these analogues in order to develop them as drug candidates for malaria.
疟原虫利用肌动蛋白动力学进行运动，而这些动力学的任何破坏都会使疟原虫无法有效建立感染。因此，肌动蛋白是疟疾药物研发的一个潜在靶点，天然存在的肌动蛋白抑制剂如拉春库林是一个有前景的起点。然而，天然产物的有限可用性以及拉春库林合成路线的繁琐阻碍了它们作为候选药物的潜在开发。在这方面，我们最近描述了新型截短的拉春库林，其对恶性疟原虫肌动蛋白的肌动蛋白结合能力和选择性优于经典的拉春库林B。在本文中，我们进一步探索截短的拉春库林核心，以总结抑制疟疾运动的构效关系。这项研究有助于进一步了解这些类似物的结合模式，以便将它们开发为疟疾的候选药物。
