scholarly journals Characterization of apo-form selective inhibition of indoleamine 2,3-dioxygenase

2018 ◽  
Author(s):  
Rodrigo Ortiz-Meoz ◽  
Liping Wang ◽  
Rosalie Matico ◽  
Anna Rutkowska ◽  
Martha De la Rosa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Kynurenine Pathway ◽  
Cellular Systems ◽  
Inhibition Mechanism ◽  
Pharmacokinetic Parameters ◽  
Indoleamine 2,3 Dioxygenase ◽  
Disease States ◽  
Rate Limiting Step

ABSTRACTIndoleamine-2,3-dioxygenase 1 (IDO1) is a heme-containing enzyme that catalyzes the rate-limiting step in the kynurenine pathway of tryptophan (TRP) metabolism. As an inflammation-induced immunoregulatory enzyme, pharmacological inhibition of IDO1 activity is currently being pursued as a potential therapeutic tool for the treatment of cancer and other disease states. As such, a detailed understanding of the mechanism of action of established and novel IDO1 inhibitors remains of great interest. Comparison of a newly-developed IDO1 inhibitor (GSK5628) to the existing best-in-class compound, epacadostat (Incyte), allows us to report on a unique inhibition mechanism for IDO1. Here, we demonstrate that GSK5628 inhibits IDO1 by competing with heme for binding to a heme-free conformation of the enzyme (apo-IDO1) while epacadostat coordinates its binding with the iron atom of the IDO1 heme cofactor. Comparison of these two compounds in cellular systems reveals a long-lasting inhibitory effect of GSK5628, undescribed for other known IDO1 inhibitors. Detailed characterization of this apo-binding mechanism for IDO1 inhibition may help design superior inhibitors or may confer a unique competitive advantage over other IDO1 inhibitors vis-à-vis specificity and pharmacokinetic parameters.

scholarly journals What is the prospect of indoleamine 2,3-dioxygenase 1 inhibition in cancer? Extrapolation from the past

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Yu Yao ◽  
Heng Liang ◽  
Xin Fang ◽  
Shengnan Zhang ◽  
Zikang Xing ◽  
...  
Keyword(s):  
Predictive Biomarkers ◽  
Kynurenine Pathway ◽  
Phase Iii ◽  
Current Status ◽  
The Past ◽  
Indoleamine 2,3 Dioxygenase ◽  
Negative Results ◽  
Rate Limiting Step ◽  
Pharmacodynamic Markers ◽  
Tumor Types

AbstractIndoleamine 2,3-dioxygenase 1 (IDO1), a monomeric heme-containing enzyme, catalyzes the first and rate-limiting step in the kynurenine pathway of tryptophan metabolism, which plays an important role in immunity and neuronal function. Its implication in different pathophysiologic processes including cancer and neurodegenerative diseases has inspired the development of IDO1 inhibitors in the past decades. However, the negative results of the phase III clinical trial of the would-be first-in-class IDO1 inhibitor (epacadostat) in combination with an anti-PD1 antibody (pembrolizumab) in patients with advanced malignant melanoma call for a better understanding of the role of IDO1 inhibition. In this review, the current status of the clinical development of IDO1 inhibitors will be introduced and the key pre-clinical and clinical data of epacadostat will be summarized. Moreover, based on the cautionary notes obtained from the clinical readout of epacadostat, strategies for the identification of reliable predictive biomarkers and pharmacodynamic markers as well as for the selection of the tumor types to be treated with IDO1inhibitors will be discussed.

Oxidation of L-tryptophan in biology: a comparison between tryptophan 2,3-dioxygenase and indoleamine 2,3-dioxygenase

2009 ◽  
Vol 37 (2) ◽  
pp. 408-412 ◽  
Author(s):  
Sara A. Rafice ◽  
Nishma Chauhan ◽  
Igor Efimov ◽  
Jaswir Basran ◽  
Emma Lloyd Raven
Keyword(s):  
Structural Information ◽  
Recombinant Expression ◽  
Kynurenine Pathway ◽  
Expression Systems ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
The Family ◽  
And Function ◽  
Rate Limiting

The family of haem dioxygenases catalyse the initial oxidative cleavage of L-tryptophan to N-formylkynurenine, which is the first, rate-limiting, step in the L-kynurenine pathway. In the present paper, we discuss and compare structure and function across the family of haem dioxygenases by focusing on TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase), including a review of recent structural information for both enzymes. The present paper describes how the recent development of recombinant expression systems has informed our more detailed understanding of the substrate binding, catalytic activity and mechanistic properties of these haem dioxygenases.

scholarly journals Characterization of Apo‐Form Selective Inhibition of Indoleamine 2,3‐Dioxygenase**

ChemBioChem ◽  
2020 ◽  
Author(s):  
Rodrigo F. Ortiz‐Meoz ◽  
Liping Wang ◽  
Rosalie Matico ◽  
Anna Rutkowska‐Klute ◽  
Martha De la Rosa ◽  
...  
Keyword(s):  
Selective Inhibition ◽  
Indoleamine 2,3 Dioxygenase

scholarly journals Partial Characterization of Protease Inhibitors of Ulva ohnoi and Their Effect on Digestive Proteases of Marine Fish

Marine Drugs ◽  
2020 ◽  
Vol 18 (6) ◽  
pp. 319
Author(s):  
Antonio Jesús Vizcaíno ◽  
Alba Galafat ◽  
María Isabel Sáez ◽  
Tomás Francisco Martínez ◽  
Francisco Javier Alarcón
Keyword(s):  
Protease Inhibitors ◽  
Marine Fish ◽  
Inhibitory Effect ◽  
Inhibition Mechanism ◽  
Digestive Proteases ◽  
Reference Protein ◽  
Ulva Ohnoi ◽  
Hydrolysis Of

This piece of research evaluates the presence of protease inhibitors in the macroalga Ulva ohnoi and provides an initial overview of their mode of action. The ability of Ulva protease inhibitors to inhibit digestive proteases of three marine fish species, as well as their capacity to hamper the hydrolysis of a reference protein by those fish proteases, were assessed. In addition, thermal stability and the mode of inhibition on trypsin and chymotrypsin were also studied. Dose-response inhibition curves and in vitro protein hydrolysis assays revealed a noticeable inhibition of fish enzymes when Ulva concentration increased in the assay. The thermal treatment of Ulva reduced markedly the inhibitory effect on fish digestive protease. Finally, Lineweaver–Burk plots indicated that trypsin and chymotrypsin inhibition consisted of a mixed-type inhibition mechanism in which the inhibitory effect depends on Ulva concentration. Overall, the results confirmed the presence of protease inhibitors in Ulva, though heat treatment was enough for inactivating these compounds.

scholarly journals Exploring the mechanism of tryptophan 2,3-dioxygenase

2008 ◽  
Vol 36 (6) ◽  
pp. 1120-1123 ◽  
Author(s):  
Sarah J. Thackray ◽  
Christopher G. Mowat ◽  
Stephen K. Chapman
Keyword(s):  
Catalytic Mechanism ◽  
Kynurenine Pathway ◽  
Oxidation Catalysts ◽  
Function Structure ◽  
Indoleamine 2,3 Dioxygenase ◽  
Rate Limiting Step ◽  
Limiting Step ◽  
Biochemical Analyses ◽  
Rate Limiting ◽  
Haem Proteins

The haem proteins TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) are specific and powerful oxidation catalysts that insert one molecule of dioxygen into L-tryptophan in the first and rate-limiting step in the kynurenine pathway. Recent crystallographic and biochemical analyses of TDO and IDO have greatly aided our understanding of the mechanisms employed by these enzymes in the binding and activation of dioxygen and tryptophan. In the present paper, we briefly discuss the function, structure and possible catalytic mechanism of these enzymes.

Characterization of Thromboxane A2/Prostaglandin H2 Receptors in Porcine Coronary Artery -The Inhibitory Effect of a Novel Dibenzoxepin Derivative, KW-3635

1992 ◽  
Vol 67 (05) ◽  
pp. 582-584 ◽  
Author(s):  
Ichiro Miki ◽  
Akio Ishii
Keyword(s):  
Coronary Artery ◽  
Binding Sites ◽  
Thromboxane A2 ◽  
Inhibitory Effect ◽  
Scatchard Analysis ◽  
Single Class ◽  
Porcine Coronary Artery ◽  
Equilibrium Binding ◽  
H2 Receptors

SummaryWe characterized the thromboxane A2/prostaglandin H2 receptors in porcine coronary artery. The binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to coronary arterial membranes was saturable and displaceable. Scatchard analysis of equilibrium binding showed a single class of high affinity binding sites with a dissociation constant of 18.5 ±1.0 nM and the maximum binding of 80.7 ± 5.2 fmol/mg protein. [3H]SQ 29,548 binding was concentration-dependently inhibited by thromboxane A2 antagonists such as SQ 29,548, BM13505 and BM13177 or the thromboxane A2 agonists such as U46619 and U44069. KW-3635, a novel dibenzoxepin derivative, concentration-dependently inhibited the [3H]SQ 29,548 binding to thromboxane A2/prosta-glandin H2 receptors in coronary artery with an inhibition constant of 6.0 ± 0.69 nM (mean ± S.E.M.).

Selective Inhibition of Thromboxane Synthetase with Dazoxiben - Basis of Its Inhibitory Effect on Platelet Adhesion

1983 ◽  
Vol 49 (02) ◽  
pp. 096-101 ◽  
Author(s):  
V C Menys ◽  
J A Davies
Keyword(s):  
Arachidonic Acid ◽  
Platelet Adhesion ◽  
Fold Increase ◽  
Selective Inhibition ◽  
Inhibitory Effect ◽  
Selective Inhibitor ◽  
Coated Glass ◽  
Thromboxane Synthetase ◽  
Pre Treatment

SummaryPlatelet adhesion to rabbit aortic subendothelium or collagen-coated glass was quantitated in a rotating probe device by uptake of radio-labelled platelets. Under conditions in which aspirin had no effect, dazoxiben, a selective inhibitor of thromboxane synthetase, reduced platelet adhesion to aortic subendothelium by about 40% but did not affect adhesion to collagen-coated glass. Pre-treatment of aortic segments with 15-HPETE, a selective inhibitor of PGI2-synthetase, abolished the inhibitory effect of dazoxiben on adhesion. Concentrations of 6-oxo-PGFlα in the perfusate were raised in the presence of dazoxiben alone, and following addition of thrombin (10 units/ml) there was a 2-3 fold increase in concentration. Perfusion of damaged aorta with platelets labelled with (14C)-arachidonic acid in the presence of thrombin and dazoxiben resulted in the appearance of (14C)-labelled-6-oxo-PGFiα. Inhibition of thromboxane synthetase limits platelet adhesion probably by promoting vascular synthesis of PGI2 from endoperoxides liberated from adherent platelets, which subsequently promotes detachment of cells from the surface.

Kinetic Characterization of Anticarsia gemmatalis Digestive Serine- Proteases and the Inhibitory Effect of Synthetic Peptides

2018 ◽  
Vol 24 (11) ◽  
Author(s):  
Adriana M. Patarroyo-Vargas ◽  
Yaremis B. Merino-Cabrera ◽  
Jose C. Zanuncio ◽  
Francelina Rocha ◽  
Wellington G. Campos ◽  
...  
Keyword(s):  
Synthetic Peptides ◽  
Serine Proteases ◽  
Inhibitory Effect ◽  
Anticarsia Gemmatalis ◽  
Kinetic Characterization

scholarly journals Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3737
Author(s):  
Joana Moreira ◽  
Joana Almeida ◽  
Lucília Saraiva ◽  
Honorina Cidade ◽  
Madalena Pinto
Keyword(s):  
Antitumor Agents ◽  
P53 Protein ◽  
Cancer Therapeutics ◽  
Tp53 Gene ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
P53 Pathway ◽  
Protein Inhibition ◽  
In Silico Studies ◽  
Binding Cleft

The p53 protein is one of the most important tumor suppressors that are frequently inactivated in cancer cells. This inactivation occurs either because the TP53 gene is mutated or deleted, or due to the p53 protein inhibition by endogenous negative regulators, particularly murine double minute (MDM)2. Therefore, the reestablishment of p53 activity has received great attention concerning the discovery of new cancer therapeutics. Chalcones are naturally occurring compounds widely described as potential antitumor agents through several mechanisms, including those involving the p53 pathway. The inhibitory effect of these compounds in the interaction between p53 and MDM2 has also been recognized, with this effect associated with binding to a subsite of the p53 binding cleft of MDM2. In this work, a literature review of natural and synthetic chalcones and their analogues potentially interfering with p53 pathway is presented. Moreover, in silico studies of drug-likeness of chalcones recognized as p53–MDM2 interaction inhibitors were accomplished considering molecular descriptors, biophysiochemical properties, and pharmacokinetic parameters in comparison with those from p53–MDM2 in clinical trials. With this review, we expect to guide the design of new and more effective chalcones targeting the p53 pathway.

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