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Nucleoside ribohydrolases as targets for Trichomonas vaginalis therapeutic agents. This project will evaluate two essential nucleoside ribohydrolase enzymes as targets for novel antitrichomonal drugs.

核苷核糖水解酶作为阴道毛滴虫治疗剂的靶标。

基本信息

批准号：
9377339
负责人：
Brian J Stockman
金额：
$ 31.09万
依托单位：
ADELPHI UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2021-12-31
项目状态：
已结题

项目摘要

PROJECT SUMMARY Trichomoniasis is the most prevalent non-viral sexually transmitted disease. Although clinical manifestations of infection are typically mild, the immune system can be concomitantly compromised. Individuals with trichomonal infections have a higher susceptibility to more serious conditions such as cervical cancer, HIV-1, and pelvic inflammatory disease. More recently, trichomonal infection has also been associated with prostate cancer and benign prostatic hyperplasia. The causative agent is the parasitic protozoan Trichomonas vaginalis. Resistance to the existing 5-nitroimidazole class of antitrichomonal drugs has increased markedly in recent years indicating the need for new therapies with novel mechanisms of action. Nucleoside salvage pathway enzymes required by T. vaginalis represent excellent targets for developing novel antitrichomonal agents. The first step in this pathway is the hydrolysis of nucleosides to release the nucleobases. The essential enzymes adenosine/guanosine preferring nucleoside ribohydrolase (AGNH) and uridine nucleoside ribohydrolase (UNH) have been characterized and found to have distinct substrate specificities. Inhibitors of both enzymes were identified using NMR-based activity assays to screen the NIH Clinical Collection. Lack of any significant structural relationship between the two sets of inhibitors further indicates that the two ribohydrolase enzymes are distinct, druggable targets. However, the inhibitors identified from the limited chemistry space sampled by the NIH Clinical Collection have low ligand efficiencies and are thus poor starting points for developing the chemical tools needed for target validation. This project will circumvent this limitation by using a fragment-based approach to define the most critical enzyme/inhibitor interactions. A fragment diversity library encompasses a much broader chemistry space than is contained within the NIH Clinical Collection and will provide the optimal starting points for developing target validation chemical tools. The specific aims of this proposal are: 1) To identify ligand- efficient fragment inhibitors of AGNH and UNH; 2) To identify chemical tools for both AGNH and UNH with IC50 values < 1 M; and 3) To validate AGNH and UNH as targets by demonstrating a correlation between enzyme inhibition and antitrichomonal activity. The proposed studies will utilize established NMR methods, computational and medicinal chemistry, and T. vaginalis growth inhibition assays. The overall long-term goals of this project are to validate AGNH and UNH as molecular targets for novel antitrichomonal agents, and to identify inhibitors of these enzymes that possess efficacy against both 5- nitroimidazole-sensitive and 5-nitroimidazole-resistant strains of T. vaginalis.

项目总结

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A riboside hydrolase that salvages both nucleobases and nicotinamide in the auxotrophic parasite Trichomonas vaginalis.

DOI：
10.1016/j.jbc.2023.105077
发表时间：
2023-09
期刊：
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子：
4.8
作者：
Patrone, Marco;Galasyn, Gregory S.;Kerin, Fiona;Nyitray, Mattias M.;Parkin, David W.;Stockman, Brian J.;Degano, Massimo
通讯作者：
Degano, Massimo

NMR-Based Activity Assays for Determining Compound Inhibition, IC50 Values, Artifactual Activity, and Whole-Cell Activity of Nucleoside Ribohydrolases.

基于 NMR 的活性测定，用于确定核苷核糖水解酶的化合物抑制、IC50 值、人工活性和全细胞活性。

DOI：
10.3791/59928
发表时间：
2019
期刊：
Journal of visualized experiments : JoVE
影响因子：
0
作者：
Stockman,BrianJ;Kaur,Abinash;Persaud,JuliaK;Mahmood,Maham;Thuilot,SamanthaF;Emilcar,MelissaB;Canestrari,Madison;Gonzalez,JulianaA;Auletta,Shannon;Sapojnikov,Vital;Caravan,Wagma;Muellers,SamanthaN
通讯作者：
Muellers,SamanthaN

Parasitology assays to assess Trichomonas vaginalis nucleoside ribohydrolase inhibitors.

评估阴道毛滴虫核苷核糖水解酶抑制剂的寄生虫学测定。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Chimarios,Maria;Ventura,Carlos;Stockman,BrianJ
通讯作者：
Stockman,BrianJ

Structure-activity relationships for several series of fragment-based inhibitors that target Trichomonas vaginalis nucleoside ribohydrolase enzymes.

针对阴道毛滴虫核苷核糖水解酶的几个基于片段的抑制剂的结构-活性关系。

DOI：
发表时间：
2022
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
Saljanin,Edina;Ajmal,Erum;Vanegas,Davi;VanAlstine-Parris,Melissa;Stockman,Brian
通讯作者：
Stockman,Brian

Direct Measurement of Nucleoside Ribohydrolase Enzyme Activities in Trichomonas vaginalis Cells Using 19F and 13C-Edited 1H NMR Spectroscopy.

使用 19F 和 13C 编辑的 1H NMR 光谱直接测量阴道毛滴虫细胞中的核苷核糖水解酶活性。

DOI：
10.1021/acs.analchem.2c05330
发表时间：
2023
期刊：
Analytical chemistry
影响因子：
7.4
作者：
Stockman,BrianJ;Ventura,CarlosA;Deykina,ValerieS;KhayanLontscharitsch,Nickolas;Saljanin,Edina;Gil,Ari;Canestrari,Madison;Mahmood,Maham
通讯作者：
Mahmood,Maham