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关于针对念珠菌病设计的药物对果糖二磷酸醛缩酶(Fba1)和丙酮酸激酶(Pk)的新见解。

New insights on Drug's design against candidiasis on the fructose biphosphate aldolase (Fba1) and the pyruvate kinase (Pk) of .

作者信息

Maqueda-Cabrera Edson E, Castillo-Baltazar Alejandro, Vázquez-López Nancy A, Almanza-Villegas Maritza, Ramírez-Apan María Teresa, Ortega-Alfaro M Carmen, López-Cortés José G, Moreno Abel, Cuéllar-Cruz Mayra

机构信息

Departamento de Biología, División de Ciencias Naturales y Exactas, Campus Guanajuato, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, C.P. 36050, Guanajuato, Guanajuato, México.

Instituto de Química, Universidad Nacional Autónoma de México, Av. Universidad 3000, Ciudad Universitaria, Ciudad de México, C.P. 04510, México.

出版信息

Biochem Biophys Rep. 2025 Jul 25;43:102175. doi: 10.1016/j.bbrep.2025.102175. eCollection 2025 Sep.

Abstract

is well known to be the second most common cause of invasive candidiasis (IC) within immunocompromised and hospitalized patients, after . species adhere to host cells and implanted medical devices by means of cell wall proteins (CWP), of which the moonlight proteins have recently been described and are of particular importance because they have been identified in response to various virulence and/or pathogenic factors. Among the identified CWP moonlights, fructose-bisphosphate aldolase (Fba1) and pyruvate kinase (Pk) have been observed to confer immune protection against and in a mouse model. In other pathogens, these proteins have been used as therapeutic targets. As the treatment of IC has been based on four main drug classes for decades, the species has developed resistance mechanisms. In addition, has an innate resistance to the antifungal drugs, which makes the treatment of IC by this pathogen difficult. It is essential to have new formulations that allow new treatments of patients affected by this pathogen, so new targets with antifungal activity is of primary necessity. For this purpose, in this study we propose the moonlight CWPs Fba1 and Pk as novel candidates for drug targets. Using structural modeling, virtual database analysis, susceptibility tests, and enzymatic activity assays, we propose the use of new chemical molecules as potential antifungals against . In this sense, we chose to evaluate three chemical molecules (FE1, FE2 and FE3), whose chemical structure gives them the possible molecular leadership against Fba1 and Pk. Through the susceptibility experiments, our data showed that of the three molecules evaluated, FE1 was the best ligand against . We also found that Fba1 and Pk of had the characteristics of therapeutic targets against IC. In the present work, considering a group of tools and experiments it was possible to identify the best candidate molecule as a possible antifungal for the treatment of IC caused by

摘要

众所周知,在免疫功能低下和住院患者中,它是侵袭性念珠菌病(IC)的第二大常见病因,仅次于…… 该菌种通过细胞壁蛋白(CWP)粘附于宿主细胞和植入的医疗设备,其中月光蛋白最近已被描述,并且特别重要,因为它们已被确定与各种毒力和/或致病因素有关。在已鉴定的CWP月光蛋白中,已观察到果糖 - 二磷酸醛缩酶(Fba1)和丙酮酸激酶(Pk)在小鼠模型中赋予针对……的免疫保护。在其他病原体中,这些蛋白质已被用作治疗靶点。由于几十年来IC的治疗一直基于四大类药物,该菌种已产生耐药机制。此外,…… 对抗真菌药物具有天然耐药性,这使得用这种病原体治疗IC变得困难。拥有能够对受这种病原体影响的患者进行新治疗的新制剂至关重要,因此具有抗真菌活性的新靶点是首要必需的。为此,在本研究中,我们提出月光CWP Fba1和Pk作为药物靶点的新候选物。通过结构建模、虚拟数据库分析、……药敏试验和酶活性测定,我们提出使用新的化学分子作为针对……的潜在抗真菌剂。从这个意义上说,我们选择评估三种化学分子(FE1、FE2和FE3),它们的化学结构使其有可能对Fba1和Pk具有分子优势。通过药敏实验,我们的数据表明,在评估的三种分子中,FE1是针对……的最佳配体。我们还发现……的Fba1和Pk具有针对IC的治疗靶点特征。在目前的工作中,考虑到一组工具和实验,有可能确定最佳候选分子作为治疗由……引起的IC的可能抗真菌剂

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d9b5/12318263/0140a084842f/ga1.jpg

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