Tassone Giusy, Landi Giacomo, Linciano Pasquale, Francesconi Valeria, Tonelli Michele, Tagliazucchi Lorenzo, Costi Maria Paola, Mangani Stefano, Pozzi Cecilia
Department of Biotechnology, Chemistry and Pharmacy, Department of Excellence 2018-2022, University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
Department of Life Science, University of Modena and Reggio Emilia, via Campi 103, 41125 Modena, Italy.
Pharmaceuticals (Basel). 2021 Jun 30;14(7):636. doi: 10.3390/ph14070636.
and parasites are the etiological agents of various threatening neglected tropical diseases (NTDs), including human African trypanosomiasis (HAT), Chagas disease, and various types of leishmaniasis. Recently, meaningful progresses in the treatment of HAT, due to (), have been achieved by the introduction of fexinidazole and the combination therapy eflornithine-nifurtimox. Nevertheless, due to drug resistance issues and the exitance of animal reservoirs, the development of new NTD treatments is still required. For this purpose, we explored the combined targeting of two key folate enzymes, dihydrofolate reductase (DHFR) and pteridine reductase 1 (PTR1). We formerly showed that the DHFR inhibitor cycloguanil (CYC) also targets PTR1, although with reduced affinity. Here, we explored a small library of CYC analogues to understand how their substitution pattern affects the inhibition of both PTR1 and DHFR. Some novel structural features responsible for an improved, but preferential, ability of CYC analogues to target PTR1 were disclosed. Furthermore, we showed that the known drug pyrimethamine (PYR) effectively targets both enzymes, also unveiling its binding mode to PTR1. The structural comparison between PYR and CYC binding modes to PTR1 and DHFR provided key insights for the future design of dual inhibitors for HAT therapy.
寄生虫是多种具有威胁性的被忽视热带病（NTDs）的病原体，包括人类非洲锥虫病（HAT）、恰加斯病和各种类型的利什曼病。最近，由于（），通过引入非昔硝唑和依氟鸟氨酸-硝呋替莫联合疗法，HAT的治疗取得了有意义的进展。然而，由于耐药性问题以及动物宿主的存在，仍然需要开发新的NTD治疗方法。为此，我们探索了对两种关键叶酸酶二氢叶酸还原酶（DHFR）和蝶啶还原酶1（PTR1）的联合靶向作用。我们之前表明，DHFR抑制剂环氯胍（CYC）也靶向PTR1，尽管亲和力较低。在这里，我们研究了一个CYC类似物的小型文库，以了解它们的取代模式如何影响对PTR1和DHFR的抑制作用。揭示了一些负责改善CYC类似物靶向PTR1能力的新结构特征，不过这种改善具有选择性。此外，我们表明已知药物乙胺嘧啶（PYR）能有效靶向这两种酶，还揭示了其与PTR1的结合模式。PYR和CYC与PTR1和DHFR的结合模式之间的结构比较为未来设计用于HAT治疗的双重抑制剂提供了关键见解。
