Synthesis, biological evaluation and structure-activity relationships inhibitors of lipid A biosynthesis

脂质A生物合成抑制剂的合成、生物学评价及构效关系

• 批准号: 258378720
• 负责人: Professor Dr. Ralph Holl
• 金额: --
• 依托单位: Institut für Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2014
• 资助国家: 德国
• 起止时间: 2013-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/258378720?language=en
• 关键词: Synthesis; biological; evaluation; structure; activity

The growing number of multiresistant bacteria urgently necessitates novel antibiotics with a so far unexploited mechanism of action. The inhibition of the biosynthesis of lipid A represents a starting-point for the development of antibiotics against Gram-negative bacteria. The enzyme LpxC catalyzes the first committed step of lipid A biosynthesis and could be validated as an antibacterial drug target. Starting from LpxC inhibitors which were synthesized in our group, conformationally restricted as well as flexible benzyloxyacetic acid derivatives with an optimized inhibitory activity against the deacetylase, an improved antibacterial activity against a broad spectrum of Gram-negative bacteria and a high metabolic stability shall be developed. Supported by molecular docking studies, the zinc-binding group, the central ether core and the lipophilic side-chain, which represent the three main structural elements of the inhibitors, will be independently varied and the resulting compounds will be tested for their antibiotic activities. Relationships between their inhibitory activity against isolated LpxC and their structure (including stereochemistry) will be established. As the LpxC enzyme assay requires the expensive natural substrate of LpxC, an artificial substrate shall be deduced from the structure of the optimized inhibitors and will be optimized for its use in the enzyme assay. Additionally, the preparation of E. coli LpxC as well as of the enzyme from other Gram-negative bacterial species shall be facilitated by employing autodisplay.In order to inhibit lipid A synthesis more effectively, inhibitors of LpxA, another enzyme of the biosynthesis, will be developed. For this purpose virtual screening will be employed and the synthesis of peptidomimetics is envisaged.

越来越多的多重耐药细菌迫切需要新的抗生素与迄今尚未开发的作用机制。脂质A的生物合成的抑制代表了开发针对革兰氏阴性菌的抗生素的起点。酶LpxC催化脂质A生物合成的第一个关键步骤，并且可以被验证为抗菌药物靶标。从我们小组合成的LpxC抑制剂开始，应当开发具有针对脱乙酰酶的优化抑制活性、针对广谱革兰氏阴性菌的改善的抗菌活性和高代谢稳定性的构象受限的以及柔性的苄氧基乙酸衍生物。在分子对接研究的支持下，代表抑制剂三个主要结构元素的锌结合基团、中心醚核和亲脂性侧链将独立变化，并将测试所得化合物的抗生素活性。将建立它们对分离的LpxC的抑制活性与它们的结构（包括立体化学）之间的关系。由于LpxC酶测定需要昂贵的LpxC天然底物，因此应从优化的抑制剂的结构推导出人工底物，并对其在酶测定中的使用进行优化。此外，对E.为了更有效地抑制脂质A的合成，将开发另一种生物合成酶LpxA的抑制剂。为此目的，将采用虚拟筛选，并设想合成肽模拟物。

项目成果

LpxC inhibitors: a patent review (2010-2016)

• DOI: 10.1080/13543776.2017.1360282
• 发表时间: 2017-01-01
• 期刊: EXPERT OPINION ON THERAPEUTIC PATENTS
• 影响因子: 6.6
• 作者: Kalinin, Dmitrii V.;Holl, Ralph
• 通讯作者: Holl, Ralph

Synthesis and biological evaluation of enantiomerically pure glyceric acid derivatives as LpxC inhibitors.

• DOI: 10.1016/j.bmc.2016.01.029
• 发表时间: 2016-03
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Giovanni Tangherlini;T. Torregrossa;Oriana Agoglitta;Jens Köhler;Jelena Melesina;W. Sippl;Ralph Holl

Synthesis and biological evaluation of C -ethynyl furanosides as LpxC inhibitors

• DOI: 10.1016/j.tet.2014.12.069
• 发表时间: 2015-02
• 期刊: Tetrahedron
• 影响因子: 2.1
• 作者: S. Jana;Marius Löppenberg;C. Daniliuc;Ralph Holl

Chiral pool synthesis and biological evaluation of C-furanosidic and acyclic LpxC inhibitors.

• DOI: 10.1016/j.ejmech.2016.01.032
• 发表时间: 2016-03
• 期刊: European journal of medicinal chemistry
• 影响因子: 6.7
• 作者: H. Müller;V. Gabrielli;Oriana Agoglitta;Ralph Holl