Covalent Small Molecule Immunomodulators Targeting the Protease Active Site

Kim, Hong Rae; Tagirasa, Ravichandra; Yoo, Euna

doi:10.1021/acs.jmedchem.1c00172

Cited by 16 publications

(14 citation statements)

References 276 publications

(500 reference statements)

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“…Moreover, similar results were obtained on lipopolysaccharidestimulated macrophages. 29 In the anti-inflammatory experiment, bovine serum albumin was used for protein denaturation, which causes © 2023 the authors. This work is licensed under the Creative Commons Attribution 4.0 International License functionality loss 30 .…”

Section: Resultsmentioning

confidence: 99%

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

2023

TJNPR

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Protease inhibitors have considerable applications in biomedicine, biotechnology, and therapy. The aim of the study was to evaluate the methanol crude extracts of aerial portions of Portulaca oleracea (P. oleracea) for anti-inflammatory, antioxidant, and protease inhibitor activities, and to evaluate their inhibitory action against various therapeutically significant proteases. A modified colorimetric assay was used to analyze the protease inhibitors on trypsin and other therapeutic enzymes. P. oleracea crude leaf extract exhibited 79.92% antioxidant and 75% anti-inflammatory activity. Analysis of the effects of crude P. oleracea extract on the values of enzyme kinetics (Km, Vmax) was determined by Lineweaver-Burk reciprocal plot. It was found that the extract exhibited a potent inhibitory effect on the Vmax (µmole/min) of the chymotrypsin 26.0, trypsin 18.0, papain 8.33, and elastase 10.0, when compared to control 41.0, 73.0, 11.11, and 20.3, respectively. While no effect on Km except for elastase which was decreased from 0.026 mM for the control to 0.01 mM. It was found that this effect showed a powerful inhibition in a different way. There is a mixed non-competitive inhibition on elastase as well as pure non-competitive inhibition on chymotrypsin, trypsin, and papain. The crude extract contained 53.3%, 55.7%, 14.9%, and 26.9%, respectively, of protease inhibitors for the therapeutic protease enzymes trypsin, papain, chymotrypsin, and elastase. Therefore, trypsin, papain, chymotrypsin, and elastase have been inhibited by the crude extract of P. oleracea. Characterization of the crude extract indicated potent anti-inflammatory and antioxidant effects.

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Section: Resultsmentioning

confidence: 99%

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

2023

TJNPR

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“…In recent times, covalent inhibitors have gained momentum owing to their potency, selectivity and extended duration of action (Kim et al, 2021;Gao et al, 2022). Covalent inhibitors have an electrophilic warhead that reacts with nucleophilic residues, both reversibly and irreversibly (Kumalo et al, 2015;A ́brańyi-Balogh and Keserű, 2022).…”

Section: B a Figurementioning

confidence: 99%

Integration of molecular modelling and in vitro studies to inhibit LexA proteolysis

Schuurs

McDonald²,

Croft³

et al. 2023

Front. Cell. Infect. Microbiol.

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IntroductionAs antibiotic resistance has become more prevalent, the social and economic impacts are increasingly pressing. Indeed, bacteria have developed the SOS response which facilitates the evolution of resistance under genotoxic stress. The transcriptional repressor, LexA, plays a key role in this response. Mutation of LexA to a non-cleavable form that prevents the induction of the SOS response sensitizes bacteria to antibiotics. Achieving the same inhibition of proteolysis with small molecules also increases antibiotic susceptibility and reduces drug resistance acquisition. The availability of multiple LexA crystal structures, and the unique Ser-119 and Lys-156 catalytic dyad in the protein enables the rational design of inhibitors.MethodsWe pursued a binary approach to inhibit proteolysis; we first investigated β-turn mimetics, and in the second approach we tested covalent warheads targeting the Ser-119 residue. We found that the cleavage site region (CSR) of the LexA protein is a classical Type II β-turn, and that published 1,2,3-triazole compounds mimic the β-turn. Generic covalent molecule libraries and a β-turn mimetic library were docked to the LexA C-terminal domain using molecular modelling methods in FlexX and CovDock respectively. The 133 highest-scoring molecules were screened for their ability to inhibit LexA cleavage under alkaline conditions. The top molecules were then tested using a RecA-mediated cleavage assay.ResultsThe β-turn library screen did not produce any hit compounds that inhibited RecA-mediated cleavage. The covalent screen discovered an electrophilic serine warhead that can inhibit LexA proteolysis, reacting with Ser-119 via a nitrile moiety. DiscussionThis research presents a starting point for hit-to-lead optimisation, which could lead to inhibition of the SOS response and prevent the acquisition of antibiotic resistance.

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“…We selected the tetrapeptide Ile‐Glu‐Thr‐Asp‐CHO (IETD) as a new granzyme B ligand for exploring the possibility of the granzyme B‐targeting probes. IETD is a kind of granzyme B inhibitor, and the C ‐terminal aldehyde of the peptide was reported to be important for covalent binding to granzyme B due to its high electrophilicity 9–11 . In addition, IETD is an attractive ligand to develop a granzyme B imaging probe based on the tetrapeptide inhibitor of human granzyme B.…”

Section: Introductionmentioning

confidence: 99%

“…IETD is a kind of granzyme B inhibitor, and the C-terminal aldehyde of the peptide was reported to be important for covalent binding to granzyme B due to its high electrophilicity. [9][10][11] In addition, IETD is an attractive ligand to develop a granzyme B imaging probe based on the tetrapeptide inhibitor of human granzyme B. For application to clinics, the development of a human granzyme B imaging probe is desired.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of ¹¹¹In‐labeled tetrapeptide‐based compounds as single‐photon emission computed tomography imaging probes targeting granzyme B

Kazuta,

Watanabe,

Ono

2023

Labelled Comp Radiopharmac

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Granzyme B is an attractive target as a biomarker for contributing to improve the treatment with immune checkpoint inhibitor (ICI). In this study, we designed novel 111In‐labeled granzyme B‐targeting single‐photon emission computed tomography (SPECT) imaging probes, [111In]IDT and [111In]IDAT. Nonradioactive In‐labeled granzyme B‐targeting compounds ([natIn]IDT, [natIn]IDAT) showed the affinity for recombinant mouse granzyme B. [111In]IDT and [111In]IDAT were obtained with moderate radiochemical yield and high stability in mouse plasma (>95%). In a biodistribution experiment using tumor‐bearing mice, [111In]IDT and [111In]IDAT showed moderate accumulation in tumor. Ex vivo autoradiography (ARG) indicated that the accumulation of radioactivity in tumor was correlated to expression of granzyme B confirmed by the immunohistochemical staining. These results indicated that [111In]IDT and [111In]IDAT showed the basic properties as granzyme B‐targeting SPECT probes.

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Covalent Small Molecule Immunomodulators Targeting the Protease Active Site

Cited by 16 publications

References 276 publications

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

Integration of molecular modelling and in vitro studies to inhibit LexA proteolysis

Synthesis and evaluation of ¹¹¹In‐labeled tetrapeptide‐based compounds as single‐photon emission computed tomography imaging probes targeting granzyme B

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Covalent Small Molecule Immunomodulators Targeting the Protease Active Site

Cited by 16 publications

References 276 publications

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

ERRATUM: Evaluation of the Anti-inflammatory, Antioxidant, and Protease Inhibitory Activity of the Crude Methanol Extract of Portulaca oleracea

Integration of molecular modelling and in vitro studies to inhibit LexA proteolysis

Synthesis and evaluation of 111In‐labeled tetrapeptide‐based compounds as single‐photon emission computed tomography imaging probes targeting granzyme B

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Synthesis and evaluation of ¹¹¹In‐labeled tetrapeptide‐based compounds as single‐photon emission computed tomography imaging probes targeting granzyme B