Nardella Flore, Halby Ludovic, Dobrescu Irina, Viluma Johanna, Bon Corentin, Claes Aurélie, Cadet-Daniel Véronique, Tafit Ambre, Roesch Camille, Hammam Elie, Erdmann Diane, Mairet-Khedim Melissa, Peronet Roger, Mecheri Salah, Witkowski Benoit, Scherf Artur, Arimondo Paola B
Unité Biologie des Interactions Hôte-Parasite, Département de Parasites et Insectes Vecteurs, Institut Pasteur, CNRS ERL 9195, INSERM Unit U1201, 25-28 Rue du Dr Roux, Paris 75015, France.
Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR n°3523, CNRS, 28 Rue du Dr Roux, Paris 75015, France.
J Med Chem. 2021 Jul 22;64(14):10403-10417. doi: 10.1021/acs.jmedchem.1c00821. Epub 2021 Jun 29.
Epigenetic post-translational modifications are essential for human malaria parasite survival and progression through its life cycle. Here, we present new functionalized suberoylanilide hydroxamic acid (SAHA) derivatives that chemically combine the pan-histone deacetylase inhibitor SAHA with the DNA methyltransferase inhibitor procainamide. A three- or four-step chemical synthesis was designed starting from cheap raw materials. Compared to the single drugs, the combined molecules showed a superior activity in and a potent inhibition against human HDAC6, exerting no cytotoxicity in human cell lines. These new compounds are fully active in multidrug-resistant Cambodian isolates. They target transmission of the parasite by inducing irreversible morphological changes in gametocytes and inhibiting exflagellation. The compounds are slow-acting and have an additive antimalarial effect in combination with fast-acting epidrugs and dihydroartemisinin. The lead compound decreases parasitemia in mice in a severe malaria model. Taken together, this novel fused molecule offers an affordable alternative to current failing antimalarial therapy.
表观遗传翻译后修饰对于人类疟原虫的存活及其生命周期的进展至关重要。在此，我们展示了新的功能化辛二酰苯胺异羟肟酸（SAHA）衍生物，这些衍生物将泛组蛋白去乙酰化酶抑制剂SAHA与DNA甲基转移酶抑制剂普鲁卡因酰胺进行了化学结合。从廉价原料出发设计了三步或四步化学合成方法。与单一药物相比，组合分子在体外显示出更高的活性，对人HDAC6具有强效抑制作用，在人细胞系中无细胞毒性。这些新化合物对柬埔寨多药耐药分离株具有完全活性。它们通过诱导配子体发生不可逆的形态变化并抑制配子出丝来靶向疟原虫的传播。这些化合物作用缓慢，与速效表皮药物和双氢青蒿素联合使用时具有相加抗疟作用。先导化合物在严重疟疾模型中可降低小鼠的疟原虫血症。综上所述，这种新型融合分子为当前失败的抗疟治疗提供了一种经济实惠的替代方案。
