Abstract：
Chagas disease is caused by the parasite Trypanosoma cruzi and affects over 7 million people worldwide. The two actual treatments, Benznidazole (Bzn) and Nifurtimox, cause serious side effects due to their high toxicity leading to treatment abandonment by the patients. In this work, we propose DNA G-quadruplexes (G4) as potential therapeutic targets for this infectious disease. We have found 174 PQS per 100,000 nucleotides in the genome of T. cruzi and confirmed G4 formation of three frequent motifs. We synthesized a family of 14 quadruplex ligands based in the dithienylethene (DTE) scaffold and demonstrated their binding to these identified G4 sequences. Several DTE derivatives exhibited micromolar activity against epimastigotes of four different strains of T. cruzi, in the same concentration range as Bzn. Compounds L3 and L4 presented remarkable activity against trypomastigotes, the active form in blood, of T. cruzi SOL strain (IC50 = 1.5-3.3 μM, SI = 25-40.9), being around 40 times more active than Bzn and displaying much better selectivity indexes.
摘要：
恰加斯病是由寄生虫克氏锥虫引起的，影响全球700多万人。两种实际的治疗方法，苯并硝唑（Bzn）和硝呋替莫，导致严重的副作用，因为它们的高毒性导致患者放弃治疗。在这项工作中,我们提出DNAG-四链体(G4)作为这种感染性疾病的潜在治疗靶点.我们在克氏锥虫基因组中发现了每100,000个核苷酸174个PQS，并证实了三个频繁基序的G4形成。我们合成了基于二噻吩乙烯（DTE）支架的14个四链体配体家族，并证明了它们与这些鉴定的G4序列的结合。几种DTE衍生物对四种不同品系的克氏毛虫表现出微摩尔活性，在与BZN相同的浓度范围内。化合物L3和L4对色素动物具有显着的活性，血液中的活性形式，克氏杆菌SOL菌株(IC50=1.5-3.3μM，SI=25-40.9)，活性比Bzn高40倍左右，选择性指数更好。
