Barcelona Institute for Global Health (ISGlobal), Hospital Clínic-University of Barcelona, 08036 Barcelona, Spain.
Department of Pharmacology, Toxicology, and Therapeutics, Veterinary Faculty, Autonomous University of Barcelona, 08193 Bellaterra, Spain.
Int J Mol Sci. 2021 Jan 12;22(2):688. doi: 10.3390/ijms22020688.
Chagas disease is caused by the protozoan parasite and affects over 6 million people worldwide. Development of new drugs to treat this disease remains a priority since those currently available have variable efficacy and frequent adverse effects, especially during the long regimens required for treating the chronic stage of the disease. modulates the host cell-metabolism to accommodate the cell cytosol into a favorable growth environment and acquire nutrients for its multiplication. In this study we evaluated the specific anti- activity of nine bio-energetic modulator compounds. Notably, we identified that 17-DMAG, which targets the ATP-binding site of heat shock protein 90 (Hsp90), has a very high (sub-micromolar range) selective inhibition of the parasite growth. This inhibitory effect was also highly potent (IC = 0.27 μmol L) against the amastigote intracellular replicative stage of the parasite. Moreover, molecular docking results suggest that 17-DMAG may bind Hsp90 homologue Hsp83 with good affinity. Evaluation in a mouse model of chronic infection did not show parasite growth inhibition, highlighting the difficulties encountered when going from in vitro assays onto preclinical drug developmental stages.
恰加斯病由原生动物寄生虫引起，影响全球超过 600 万人。由于现有药物的疗效各不相同，且经常出现不良反应，特别是在治疗疾病慢性阶段所需的长期治疗方案中，因此开发治疗这种疾病的新药仍然是当务之急。该寄生虫通过调节宿主细胞代谢来适应细胞胞质溶胶，为其增殖获取营养。在这项研究中，我们评估了九种生物能量调节剂化合物的特定抗活性。值得注意的是，我们发现靶向热休克蛋白 90（Hsp90）ATP 结合位点的 17-DMAG 对寄生虫的生长具有非常高（亚微摩尔范围）的选择性抑制作用。这种抑制作用对寄生虫的内阿米巴样繁殖阶段也具有很高的活性（IC = 0.27 μmol L）。此外，分子对接结果表明，17-DMAG 可能与 Hsp83 同源 HSP90 具有良好的结合亲和力。在慢性感染的小鼠模型中的评估并未显示寄生虫生长抑制，这突出了从体外测定到临床前药物开发阶段所遇到的困难。
