Barcelona Institute for Global Health (ISGlobal), Hospital Clinic - University of Barcelona, Barcelona, Spain.
Secció de Parasitologia, Departament de Biologia, Sanitat i Medi Ambient, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain.
Front Cell Infect Microbiol. 2023 Jan 13;12:1067461. doi: 10.3389/fcimb.2022.1067461. eCollection 2022.
Chagas disease is caused by the protozoan parasite , and it is the most important neglected tropical disease in the Americas. Two drugs are available to treat the infection, but their efficacy in the chronic stage of the disease, when most cases are diagnosed, is reduced. Their tolerability is also hindered by common adverse effects, making the development of safer and efficacious alternatives a pressing need. is unable to synthesize purines de novo, relying on a purine salvage pathway to acquire these from its host, making it an attractive target for the development of new drugs.
We evaluated the anti-parasitic activity of 23 purine analogs with different substitutions in the complementary chains of their purine rings. We sequentially screened the compounds' capacity to inhibit parasite growth, their toxicity in Vero and HepG2 cells, and their specific capacity to inhibit the development of amastigotes. We then used in-silico docking to identify their likely targets.
Eight compounds showed specific anti-parasitic activity, with IC values ranging from 2.42 to 8.16 μM. Adenine phosphoribosyl transferase, and hypoxanthine-guanine phosphoribosyl transferase, are their most likely targets.
Our results illustrate the potential role of the purine salvage pathway as a target route for the development of alternative treatments against infection, highlithing the apparent importance of specific substitutions, like the presence of benzene groups in the C8 position of the purine ring, consistently associated with a high and specific anti-parasitic activity.
恰加斯病是由原生动物寄生虫引起的，它是美洲最重要的被忽视的热带病。有两种药物可用于治疗感染，但在疾病的慢性阶段（大多数病例被诊断出时），其疗效降低。它们的耐受性也受到常见不良反应的阻碍，因此开发更安全、更有效的替代品迫在眉睫。 不能从头合成嘌呤，依赖嘌呤补救途径从宿主中获取这些嘌呤，这使其成为开发新药的有吸引力的目标。
我们评估了 23 种嘌呤类似物的抗寄生虫活性，这些类似物在嘌呤环的互补链中有不同的取代。我们依次筛选化合物抑制寄生虫生长的能力、在 Vero 和 HepG2 细胞中的毒性以及它们特异性抑制无鞭毛体发育的能力。然后，我们使用计算机对接来确定它们可能的靶点。
有 8 种化合物表现出特异性抗寄生虫活性，IC 值范围为 2.42 至 8.16 μM。腺嘌呤磷酸核糖基转移酶和次黄嘌呤-鸟嘌呤磷酸核糖基转移酶是它们最可能的靶点。
我们的结果说明了嘌呤补救途径作为开发替代治疗方法的潜在靶点，突出了特定取代的明显重要性，例如嘌呤环的 C8 位置存在苯基团，与高特异性抗寄生虫活性一致。
