Catalysis and inhibition of chitin synthesis from pathogenic fungi

病原真菌几丁质合成的催化和抑制

基本信息

  • 批准号:
    10501171
  • 负责人:
  • 金额:
    $ 63.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-06-07 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract The available antifungal drugs against invasive fungal infections are limited due to the challenge in selectively killing eukaryotic pathogens without harming humans. Chitin synthases (CHSs) represent one of few proven targets whose inhibition provides highly selective antifungal effects without any detectable toxicity to humans. CHSs are transmembrane processive glycosyltransferases (GTs) responsible for the biosynthesis of chitin, an essential polysaccharide component of the fungal cell wall. Due to their essential function in fungal physiology, CHSs are targeted by naturally occurring peptidyl nucleoside (PN) antifungal agents. PNs exhibit in vivo activities against multiple endemic fungal pathogens without adverse effects on humans, and exhibit a strong synergy with current FDA-approved antifungal drugs. However, their development has been slow because of only moderate antifungal activities against more clinically prevalent fungal pathogens such as Candida albicans and the absence of atomic-level understanding of CHS. Our long-term goal is to provide a comprehensive understanding of CHS catalysis, regulation, and inhibition at the atomic level. The current application focuses on structural and mechanistic studies of the catalysis and inhibition of C. albicans CHSs. C. albicans has four CHSs of which CaCHS1 and CaCH2 require simultaneous inhibition for fungicidal effects. While existing PNs potently inhibit CaCHS2, they are much weaker against CaCHS1 and thus exhibit only moderate antifungal activity against C. albicans. The molecular mechanism behind the difference in PN potency between CaCHS1 and CaCH2 is currently unknown. For the future development of CHS-targeting anti-candida agents, it is essential to understand their structural and mechanistic differences for both catalysis and inhibition. As a preliminary study, we heterologously expressed and purified catalytically active CaCHS1 and CaCHS2, and solved the cryo-EM structures of CaCHS2 in the apo-, substrate-bound, and PN (nikkomycin Z and polyoxin D)-bound forms. We also developed novel activity assays for the determination of chitin chain length and quantitation of both long insoluble chitin and short soluble chito-oligosaccharides, and established a method for chemo-enzymatic synthesis of nikkomycin analogs. Based on these developments, we propose to study the mechanism of chitin formation and extrusion by CaCHS2 (Aim 1), the functional and structural basis of the lower susceptibility of CaCHS1 to PNs as well as the synergy of using both CaCHS1 and CaCHS2 inhibitors (Aim 2), and the detailed and systematic structure-activity relationships of PNs (Aim 3). For Aims 2 and 3, clinical isolates of C. albicans and non-albicans candida strains will also be included for inhibitor testing, increasing the translational potential of our research program. The proposed research is significant because it will provide the molecular basis for future development of novel antifungals against a clinically unexploited target.
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Seok-Yong Lee其他文献

Seok-Yong Lee的其他文献

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{{ truncateString('Seok-Yong Lee', 18)}}的其他基金

Molecular principles of anti-COVID-19 drug uptake by human nucleoside transporters
人类核苷转运蛋白摄取抗COVID-19药物的分子原理
  • 批准号:
    10703355
  • 财政年份:
    2022
  • 资助金额:
    $ 63.91万
  • 项目类别:
Catalysis and inhibition of chitin synthesis from pathogenic fungi
病原真菌几丁质合成的催化和抑制
  • 批准号:
    10640198
  • 财政年份:
    2022
  • 资助金额:
    $ 63.91万
  • 项目类别:
Molecular principles of anti-COVID-19 drug uptake by human nucleoside transporters
人类核苷转运蛋白摄取抗COVID-19药物的分子原理
  • 批准号:
    10348225
  • 财政年份:
    2022
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    10403716
  • 财政年份:
    2021
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structural and Mechanistic Characterization of MraY Catalysis and Inhibition
MraY 催化和抑制的结构和机制表征
  • 批准号:
    9156353
  • 财政年份:
    2017
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    10245145
  • 财政年份:
    2016
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    10687812
  • 财政年份:
    2016
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    9761604
  • 财政年份:
    2016
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    9336001
  • 财政年份:
    2016
  • 资助金额:
    $ 63.91万
  • 项目类别:
Structure, function, and pharmacology of neuronal membrane transport proteins
神经元膜转运蛋白的结构、功能和药理学
  • 批准号:
    10472617
  • 财政年份:
    2016
  • 资助金额:
    $ 63.91万
  • 项目类别:

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