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Developing a new drug against trichomoniasis, new inhibitory compounds of the protein triosephosphate isomerase.
Parasitology International ( IF 1.9 ) Pub Date : 2020-02-27 , DOI: 10.1016/j.parint.2020.102086
José Luis Vique-Sánchez 1 , Luis Alberto Caro-Gómez 1 , Luis G Brieba 2 , Claudia G Benítez-Cardoza 1
Affiliation  

Trichomonas vaginalis is the protozoan parasite responsible for the most prevalent, non-viral, sexually transmitted disease, which affects millions of people around the world. The main treatment against this disease is metronidazole and some other nitroimidazole derivatives. However, between five and 20% of clinical cases of trichomoniasis are caused by parasites resistant to these drugs. Here we present three compounds that were selected using an innovative strategy, to propose them as possible drugs to combat trichomoniasis, using the glycolytic enzyme triose phosphate isomerase (TvTIM) as the drug target. In the genome of Trichomonas vaginalis there are two genes that encode for two isoforms of TvTIM, known as TvTIM1 and TvTIM2, varying by four out of 254 aminoacid residues. In this study, we used high-throughput virtual screening to search molecules that bind specifically to TvTIM isoforms, in which 34 compounds were selected from a library of nearly 450,000 compounds. The effects of the 34 compounds on the conformation and enzymatic activity of both TvTIM isoforms and their human homolog (HsTIM) were evaluated. We found three compounds that bind specifically, modify the conformation and inhibit TvTIM2 only; although the sequence of both isoforms of TvTIM is almost identical. The selectivity of these compounds towards TvTIM2 is explained by the lower conformational stability of this isoform and that these interactions can inhibit the activity of this enzyme and have an effect against this parasite. These compounds represent promising alternatives for the development of new therapeutic strategies against trichomoniasis.



中文翻译:

开发出一种新的抗滴虫病药物,即磷酸三糖磷酸异构酶的新抑制性化合物。

阴道毛滴虫是原生动物的寄生虫,是最普遍的,非病毒的,性传播的疾病,该病影响世界各地的数百万人。对该病的主要治疗方法是甲硝唑和其他一些硝基咪唑衍生物。但是,滴虫病的临床病例中有5%至20%是由对这些药物耐药的寄生虫引起的。在这里,我们介绍使用创新策略选择的三种化合物,以糖酵解酶磷酸三糖磷酸异构酶(TvTIM)作为药物靶标,将其作为抗滴虫病的可能药物。在阴道毛滴虫的基因组中有两个基因编码两个TvTIM亚型,分别称为TvTIM1和TvTIM2,在254个氨基酸残基中有四个相异。在这项研究中,我们使用高通量虚拟筛选来搜索与TvTIM同种型特异性结合的分子,其中从近45万种化合物的文库中选择了34种化合物。评估了34种化合物对TvTIM亚型及其人类同源物(HsTIM)的构象和酶活性的影响。我们发现了三种特异性结合,仅改变构象并仅抑制TvTIM2的化合物。尽管TvTIM的两个同工型的序列几乎相同。这些化合物对TvTIM2的选择性由该同工型的较低构象稳定性来解释,并且这些相互作用可抑制该酶的活性并对该寄生虫产生作用。这些化合物代表了针对毛滴虫病的新治疗策略开发的有希望的替代品。

更新日期:2020-02-27
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