Diseases of the Developing World (DDW), GlaxoSmithKline, Madrid, Tres Cantos 28760, Spain.
Department of Life Sciences, Imperial College of London, London SW7 2AZ, UK.
Nat Commun. 2017 May 17;8:15160. doi: 10.1038/ncomms15160.
Plasmodium falciparum stage V gametocytes are responsible for parasite transmission, and drugs targeting this stage are needed to support malaria elimination. We here screen the Tres Cantos Antimalarial Set (TCAMS) using the previously developed P. falciparum female gametocyte activation assay (Pf FGAA), which assesses stage V female gametocyte viability and functionality using Pfs25 expression. We identify over 400 compounds with activities <2 μM, chemically classified into 57 clusters and 33 singletons. Up to 68% of the hits are chemotypes described for the first time as late-stage gametocyte-targeting molecules. In addition, the biological profile of 90 compounds representing the chemical diversity is assessed. We confirm in vitro transmission-blocking activity of four of the six selected molecules belonging to three distinct scaffold clusters. Overall, this TCAMS gametocyte screen provides 276 promising antimalarial molecules with dual asexual/sexual activity, representing starting points for target identification and candidate selection.
恶性疟原虫（Plasmodium falciparum）阶段 V 配子体负责寄生虫传播，需要针对该阶段的药物来支持疟疾消除。我们使用先前开发的恶性疟原虫雌性配子体激活测定法（Pf FGAA）来筛选特雷萨坎托抗疟药集（TCAMS），该测定法使用 Pfs25 表达来评估阶段 V 雌性配子体的活力和功能。我们鉴定出超过 400 种活性低于 2 μM 的化合物，这些化合物根据化学结构分类为 57 个簇和 33 个单体。高达 68%的命中化合物为首次被描述为晚期配子体靶向分子的化学型。此外，我们评估了代表化学多样性的 90 种化合物的生物学特征。我们证实了属于三个不同支架簇的六种选定分子中的四种具有体外阻断传播的活性。总的来说，这个 TCAMS 配子体筛选提供了 276 种具有双重无性/有性活性的有前途的抗疟药物，它们是鉴定靶点和选择候选药物的起点。
