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Your search keyword '"Risa Kurimoto-Tsuruta"' showing total 3 results
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3 results on '"Risa Kurimoto-Tsuruta"'

1. Fragment-Based Discovery of Novel Non-Hydroxamate LpxC Inhibitors with Antibacterial Activity

Author

Yuya Ogata, Harumi Kanazawa, Macias Alba, Norikazu Ohtake, Allan E. Surgenor, Iichiro Takata, Hajime Takashima, Walmsley David, Kiyoko Fujita, Hayley Angove, Kunihiko Iwamoto, Masashi Mima, Hiroyuki Sugiyama, Fumihito Ushiyama, Junya Yamagishi, Yousuke Yamada, Alan P. Robertson, Kosuke Hitaka, Koichiro Nakano, Hayato Watanabe, Atsushi Okada, Yohei Matsuda, Roderick E. Hubbard, Nozomi Tanaka-Yamamoto, Toru Yamaguchi-Sasaki, Risa Kurimoto-Tsuruta, Lisa Baker, Akihiro Tanaka, and R. Harris

Subjects
Stereochemistry, chemistry.chemical_element, Zinc, Microbial Sensitivity Tests, 01 natural sciences, Amidohydrolases, Lipid A, 03 medical and health sciences, chemistry.chemical_compound, Minimum inhibitory concentration, Structure-Activity Relationship, Biosynthesis, Bacterial Proteins, Piperidines, Drug Discovery, Escherichia coli, Moiety, Chelation, Anilides, Enzyme Inhibitors, 030304 developmental biology, Chelating Agents, chemistry.chemical_classification, 0303 health sciences, Molecular Structure, Imidazoles, 0104 chemical sciences, Anti-Bacterial Agents, 010404 medicinal & biomolecular chemistry, Enzyme, chemistry, Pseudomonas aeruginosa, Molecular Medicine, Antibacterial activity
Abstract

UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a zinc metalloenzyme that catalyzes the first committed step in the biosynthesis of Lipid A, an essential component of the cell envelope of Gram-negative bacteria. The most advanced, disclosed LpxC inhibitors showing antibacterial activity coordinate zinc through a hydroxamate moiety with concerns about binding to other metalloenzymes. Here, we describe the discovery, optimization, and efficacy of two series of compounds derived from fragments with differing modes of zinc chelation. A series was evolved from a fragment where a glycine moiety complexes zinc, which achieved low nanomolar potency in an enzyme functional assay but poor antibacterial activity on cell cultures. A second series was based on a fragment that chelated zinc through an imidazole moiety. Structure-guided design led to a 2-(1S-hydroxyethyl)-imidazole derivative exhibiting low nanomolar inhibition of LpxC and a minimum inhibitory concentration (MIC) of 4 μg/mL against Pseudomonas aeruginosa, which is little affected by the presence of albumin.

Published
2020

2. Lead optimization of 2-hydroxymethyl imidazoles as non-hydroxamate LpxC inhibitors: Discovery of TP0586532

Author

Yuya Ogata, Nozomi Tanaka-Yamamoto, Naoki Sasamoto, Iichiro Takata, Katsumasa Otake, Hajime Takashima, Yohei Matsuda, Haruhiro Yamashita, Mayumi Endo, Kiyoko Fujita, Kaori Ueki, Masashi Mima, Satoshi Tsuji, Hirotoshi Okumura, Hiroyuki Sugiyama, Fumihito Ushiyama, and Risa Kurimoto-Tsuruta

Subjects
Models, Molecular, Gram-negative bacteria, Clinical Biochemistry, Drug target, Pharmaceutical Science, Carbapenem-resistant enterobacteriaceae, Microbial Sensitivity Tests, Pharmacology, Crystallography, X-Ray, 01 natural sciences, Biochemistry, Amidohydrolases, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, medicine, Escherichia coli, Hydroxymethyl, Enzyme Inhibitors, Molecular Biology, Antibacterial agent, biology, Dose-Response Relationship, Drug, Molecular Structure, 010405 organic chemistry, Chemistry, Organic Chemistry, Imidazoles, biology.organism_classification, 0104 chemical sciences, Anti-Bacterial Agents, 010404 medicinal & biomolecular chemistry, Klebsiella pneumoniae, Mechanism of action, Molecular Medicine, medicine.symptom
Abstract

Infectious diseases caused by resistant Gram-negative bacteria have become a serious problem, and the development of therapeutic drugs with a novel mechanism of action and that do not exhibit cross-resistance with existing drugs has been earnestly desired. UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) is a drug target that has been studied for a long time. However, no LpxC inhibitors are available on the market at present. In this study, we sought to create a new antibacterial agent without a hydroxamate moiety, which is a common component of the major LpxC inhibitors that have been reported to date and that may cause toxicity. As a result, a development candidate, TP0586532, was created that is effective against carbapenem-resistant Klebsiella pneumoniae and does not pose a cardiovascular risk.

Published
2020

3. Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties

Author

Risa Kurimoto-Tsuruta, Seiken Tokura, Kosuke Kanuma, Yuya Ogata, Tamaoki Tomokazu, Hiroyuki Sugiyama, Takanori Kawaguchi, Kaho Arikawa, Takeuchi Tomoki, Nozomi Tanaka-Yamamoto, Toru Yamaguchi-Sasaki, Atsushi Okada, Ippei Yoshida, Tomoko Abe-Kumasaka, Yutaka Sugaya, Ryo Takahashi, and Mitsukane Yoshinaga

Subjects
Cell Membrane Permeability, Macrocyclic Compounds, Pyrimidine, Stereochemistry, Clinical Biochemistry, Mutant, Drug Evaluation, Preclinical, Pharmaceutical Science, Molecular Dynamics Simulation, Antiviral Agents, 01 natural sciences, Biochemistry, Cell Line, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Isomerism, Drug Discovery, Animals, Humans, Moiety, Molecular Biology, chemistry.chemical_classification, Atropisomer, Binding Sites, 010405 organic chemistry, Organic Chemistry, Wild type, Virus Internalization, Fusion protein, 0104 chemical sciences, 010404 medicinal & biomolecular chemistry, Pyrimidines, chemistry, Respiratory Syncytial Virus, Human, Mutation, Pyrazoles, Molecular Medicine, Glycoprotein, Viral Fusion Proteins, Linker, Half-Life
Abstract

The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.

Published
2020

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