Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

Yan, Yu-Hang; Zhang, Ting-Ting; Li, Rong; Wang, Si-Yao; Wei, Liu-Liu; Wang, Xin-Yue; Zhu, Kai-Rong; Li, Shan-Rui; Liang, Guo-Qing; Yang, Zeng-Bao; Yang, Ling-Ling; Qin, Shangshang; Li, Guo-Bo

doi:10.1021/acs.jmedchem.3c01189

Cited by 3 publications

(2 citation statements)

References 58 publications

(188 reference statements)

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“…We subsequently evaluated the selectivity of 43 to several metalloenzymes available in our laboratory including 5 human and 10 bacterial metalloenzymes. We did not observe obvious inhibitory activities for 43 at 100 μM to bacterial monozinc (including CphA, Sfh-I) and dizinc metalloenzymes (including VIM-1, VIM-2, NDM-1, NDM-5, IMP-1, IMP-4, L1, and GOB-18). , 43 also did not show inhibition to human monozinc metalloenzyme CSN5 and dizinc metalloenzymes ecto-5′-nucleotidase (CD73) and SNM1A. Additionally, 43 have no obvious inhibition to Fe(II) heme-containing indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) (SI, Table S3).…”

Section: Resultsmentioning

confidence: 99%

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model

Mou,

Ning,

Wang

et al. 2024

J. Med. Chem.

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The secretory glutaminyl cyclase (sQC) and Golgi-resident glutaminyl cyclase (gQC) are responsible for N-terminal protein pyroglutamation and associated with various human diseases. Although several sQC/gQC inhibitors have been reported, only one inhibitor, PQ912, is currently undergoing clinic trials for the treatment of Alzheimer’s disease. We report an X-ray crystal structure of sQC complexed with PQ912, revealing that the benzimidazole makes “anchor” interactions with the active site zinc ion and catalytic triad. Structure-guided design and optimization led to a series of new benzimidazole derivatives exhibiting nanomolar inhibition for both sQC and gQC. In a MPTP-induced Parkinson’s disease (PD) mouse model, BI-43 manifested efficacy in mitigating locomotor deficits through reversing dopaminergic neuronal loss, reducing microglia, and decreasing levels of the sQC/gQC substrates, α-synuclein, and CCL2. This study not only offers structural basis and new leads for drug discovery targeting sQC/gQC but also provides evidence supporting sQC/gQC as potential targets for PD treatment.

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Section: Resultsmentioning

confidence: 99%

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model

Mou,

Ning,

Wang

et al. 2024

J. Med. Chem.

Self Cite

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“…Furthermore, a 1H-imidazole-2-carboxylic acid pharmacophore that targets Zn2 and positively charged active site residues was used to identify compound 10, which has an IC 50 value of 0.018 µM against VIM-2 and showed a 16-fold reduction in the MIC of meropenem [115]. This series was further developed to enhance potency by adding a 2-aminothiazole-4carboxylic acid core [141]. In addition, screening of a small molecule library towards IMP-1 led to the identification of 2,5-dimethyl-4-sulfamoylfuran-3-carboxylic acid (SFC) but lacked significant activity towards NDM-1 and VIM-2 [116].…”

Section: Metallo-β-lactamase Inhibitorsmentioning

confidence: 99%

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Jacobs,

Consol,

Chen

2024

Antibiotics

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform

Yan,

Wei,

et al. 2024

J. Med. Chem.

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COP9 signalosome catalytic subunit CSN5 plays a key role in tumorigenesis and tumor immunity, showing potential as an anticancer target. Currently, only a few CSN5 inhibitors have been reported, at least partially, due to the challenges in establishing assays for CSN5 deubiquitinase activity. Here, we present the establishment and validation of a simple and reliable non-catalytic activity assay platform for identifying CSN5 inhibitors utilizing a new fluorescent probe, CFP-1, that exhibits enhanced fluorescence and fluorescence polarization features upon binding to CSN5. By using this platform, we identified 2-aminothiazole-4-carboxylic acids as new CSN5 inhibitors, which inhibited CSN5 but slightly downregulated PD-L1 in cancer cells. Furthermore, through the integration of deep learning-enabled virtual screening, we discovered that shikonins are nanomolar CSN5 inhibitors, which can upregulate PD-L1 in HCT116 cells. The binding modes of these structurally distinct inhibitors with CSN5 were explored by using microsecond-scale molecular dynamics simulations and tryptophan quenching assays.

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Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-β-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding

Cited by 3 publications

References 58 publications

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model

X-ray Structure-Guided Discovery of a Potent Benzimidazole Glutaminyl Cyclase Inhibitor That Shows Activity in a Parkinson’s Disease Mouse Model

Drug Discovery in the Field of β-Lactams: An Academic Perspective

Discovering New Metallo-Deubiquitinase CSN5 Inhibitors by a Non-Catalytic Activity Assay Platform

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