scholarly journals Suppression of the Ubiquitin Pathway by Small Molecule Binding to Ubiquitin Enhances Doxorubicin Sensitivity of the Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1073 ◽  
Author(s):  
Thanh Nguyen ◽  
Minh Ho ◽  
Kyungmin Kim ◽  
Sun-Il Yun ◽  
Pushpak Mizar ◽  
...  
Keyword(s):  
Anticancer Drugs ◽  
Congo Red ◽  
Enzyme Inhibitors ◽  
Binding Activity ◽  
Diazo Compounds ◽  
Ubiquitin Pathway ◽  
Processing Enzymes ◽  
Recent Success ◽  
Promising Strategy ◽  
Ubiquitin Molecule

Development of inhibitors for ubiquitin pathway has been suggested as a promising strategy to treat several types of cancers, which has been showcased by recent success of a series of novel anticancer drugs based on inhibition of ubiquitin pathways. Although the druggability of enzymes in ubiquitin pathways has been demonstrated, ubiquitin itself, the main agent of the pathway, has not been targeted. Whereas conventional enzyme inhibitors are used to silence the ubiquitination or reverse it, they cannot disrupt the binding activity of ubiquitin. Herein, we report that the scaffolds of sulfonated aryl diazo compounds, particularly Congo red, could disrupt the binding activity of ubiquitin, resulting in the activity equivalent to inhibition of ubiquitination. NMR mapping assay demonstrated that the chemical directly binds to the recognition site for ubiquitin processing enzymes on the surface of ubiquitin, and thereby blocks the binding of ubiquitin to its cognate receptors. As a proof of concept for the druggability of the ubiquitin molecule, we demonstrated that Congo red acted as an intracellular inhibitor of ubiquitin recognition and binding, which led to inhibition of ubiquitination, and thereby, could be used as a sensitizer for conventional anticancer drugs, doxorubicin.

Effect of non-anticancer drugs on prognosis of pancreatic cancer (PaC) receiving chemotherapy.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 309-309
Author(s):  
Yousuke Nakai ◽  
Hiroyuki Isayama ◽  
Suguru Mizuno ◽  
Takashi Sasaki ◽  
Kazumichi Kawakubo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Anticancer Drugs ◽  
Enzyme Inhibitors ◽  
Angiotensin Receptor Blockers ◽  
Locally Advanced ◽  
Renin Angiotensin System ◽  
Progression Free Survival ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Receptor Blockers

309 Background: Non-anticancer drugs such as metformin or statin are reported to have a potential role in cancer treatment and we previously reported inhibition of renin-angiotensin system (RAS) by angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) lead to better prognosis in PaC receiving gemcitabine (Br J Cancer 103: 1644-8). The relation between diabetes (DM) with its medication and the incidence of PaC has been described but its impact on prognosis is still unclear. Methods: We retrospectively reviewed 250 pts with advanced PaC receiving chemotherapy with gemcitabine and/or S-1 between June 2001 and April 2011 with a median follow up of 9.9 months (Mo). Univariate and multivariate analyses of progression-free survival (PFS) and overall survival (OS) were performed in pts with and without DM, using age, gender, BMI, PS, stage, protocol, DM with its treatment, hypertension (HT) with its treatment, and use of statin as variables. Results: DM was diagnosed in 124 pts (49%) and was treated with insulin or insulin analogs (n = 59), sulfonylurea (n = 38), biguanide (n = 8), thiazolidinedione (n = 6), and alpha-glucosidase inhibitor (n = 5). Statin was used in 16 pts with DM and 14 pts without DM. Locally advanced disease (44% vs. 29%) and HT (44% vs. 28%) were more prevalent in pts with DM. PFS (6.3 vs. 4.9 Mo, P = 0.440) and OS (13.3 vs. 10.0 Mo, P = 0.084) was longer in pts with DM, though not significantly. Use of statin in pts with DM was associated with longer PFS (11.6 vs. 6.0 Mo, P = 0.034) and longer OS (25.4 vs. 11.3 Mo, P = 0.006), while PFS and OS did not differ by the use of statin in pts without DM. Multivariate subgroup analysis with and without DM showed metastatic disease (Hazard ratio [HR] 2.11, P = 0.001 and HR 1.57, P = 0.013), PS 0-1 (HR 0.08, P <0.001 and HR 0.21, P <0.001), use of ACEI/ARB (HR 0.60, P = 0.030 and HR 0.46, P = 0.031) as common prognostic factors for OS. Doublet chemotherapy (HR 0.48, P = 0.007) and use of statin (HR 0.40, P = 0.010) were prognostic only in pts with DM, but any medications for DM were not significant prognostic factors. Conclusions: In our retrospective analysis, use of statin in pts with DM as well as inhibition of RAS was associated with better prognosis in pts with PaC receiving chemotherapy.

The Synthesis of N-Ribosyl Transferase Inhibitors Based on a Transition State Blueprint

2004 ◽  
Vol 57 (9) ◽  
pp. 837 ◽  
Author(s):  
Gary B. Evans
Keyword(s):  
Transition State ◽  
Enzyme Inhibitors ◽  
Processing Enzymes ◽  
Design And Synthesis ◽  
Therapeutic Uses ◽  
Transition State Analogue ◽  
Transition State Analogue Inhibitors ◽  
State Analysis

A quarter of a century ago transition state analysis and transition state analogue design promised the prospect of extraordinarily potent enzyme inhibitors. The present overview describes the transition state analysis of a variety of N-ribosyl transferases, the design and synthesis of extremely powerful transition state analogue inhibitors of these nucleoside processing enzymes, and their current therapeutic uses and potentials.

Proteases as drug targets

2003 ◽  
Vol 70 ◽  
pp. 147-161 ◽  
Author(s):  
Andy J. Docherty ◽  
Tom Crabbe ◽  
James P. O'Connell ◽  
Colin R. Groom
Keyword(s):  
Rheumatoid Arthritis ◽  
Drug Targets ◽  
Enzyme Inhibitors ◽  
Proteolytic Enzymes ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Hiv Protease ◽  
Hiv Protease Inhibitors ◽  
Converting Enzyme Inhibitors ◽  
Recent Success ◽  
The Impact

The effective management of AIDS with HIV protease inhibitors, or the use of angiotensin-converting enzyme inhibitors to treat hypertension, indicates that proteases do make good drug targets. On the other hand, matrix metalloproteinase (MMP) inhibitors from several companies have failed in both cancer and rheumatoid arthritis clinical trials. Mindful of the MMP inhibitor experience, this chapter explores how tractable proteases are as drug targets from a chemistry perspective. It examines the recent success of other classes of drug for the treatment of rheumatoid arthritis, and highlights the need to consider where putative targets lie on pathophysiological pathways--regardless of what kind of therapeutic entity would be required to target them. With genome research yielding many possible new drug targets, it explores the likelihood of discovering proteolytic enzymes that are causally responsible for disease processes and that might therefore make better targets, especially if they lead to the development of drugs that can be administered orally. It also considers the impact that biologics are having on drug discovery, and in particular whether biologically derived therapeutics such as antibodies are likely to significantly alter the way we view proteases as targets and the methods used to discover therapeutic inhibitors.

Pyranoid Spirosugars as Enzyme Inhibitors

2020 ◽  
Vol 17 ◽  
Author(s):  
Barbara La Ferla ◽  
Giuseppe D’Orazio
Keyword(s):  
Enzyme Inhibitors ◽  
Biological Activities ◽  
Point Of View ◽  
Biologically Active ◽  
Chiral Auxiliaries ◽  
Processing Enzymes ◽  
Sugar Ring ◽  
Sugar Derivatives ◽  
Enzymatic Inhibitor ◽  
Structural Point

Background: Pyranoid spirofused sugar derivatives represent a class of compounds with a significant impact in the literature. Under the structural point of view, the rigidity inferred by the spirofused entity has made these compound object of interest mainly as enzymatic inhibitors, in particular of carbohydrate processing enzymes among which glycogen phosphorylase and sodium glucose co-transporter 2, important target enzymes for diverse pathological states. Most of the developed compounds present the spirofused entity at the C1 position of the sugar moiety, nevertheless spirofused entities can also be found at other sugar ring positions. The main spirofused entities encountered are spiroacetals/thioacetals, spiro-hydantoin and derivatives, spiro-isoxazolines, spiro-aminals, spiro-lactams, spiro-oxathiazole and spiro-oxazinanone, but also other are present. Objectives: The present review focuses on the most explored synthetic strategies for the preparation of this class of compounds, classified according to the position and structure of the spirofused moiety on the pyranoid scaffold. Moreover, the structures are correlated to their main biological activities or to their role as chiral auxiliaries. Conclusion: It is clear from the review that, among the different derivatives, the spirofused structures at position C1 of the pyranoid scaffold are the most represented and possess the most relevant enzymatic inhibitor activities. Nevertheless, great efforts have been devoted to the introduction of the spirofused entity also in the other positions, mainly for the preparation of biologically active compounds but also for the synthesis of chiral auxiliaries useful in asymmetric reactions; examples of such auxiliaries are the spirofused chiral 1,3-oxazolidin-2-ones and 1,3-oxazolidine-2-thiones.

Protein misfolding, congophilia, oligomerization, and defective amyloid processing in preeclampsia

2014 ◽  
Vol 6 (245) ◽  
pp. 245ra92-245ra92 ◽  
Author(s):  
Irina A. Buhimschi ◽  
Unzila A. Nayeri ◽  
Guomao Zhao ◽  
Lydia L. Shook ◽  
Anna Pensalfini ◽  
...  
Keyword(s):  
Congo Red ◽  
Protein Misfolding ◽  
Proteolytic Enzymes ◽  
Conformational State ◽  
Unknown Etiology ◽  
App Processing ◽  
Processing Enzymes ◽  
State Dependent ◽  
Β Amyloid ◽  
Inducible Protein

Preeclampsia is a pregnancy-specific disorder of unknown etiology and a leading contributor to maternal and perinatal morbidity and mortality worldwide. Because there is no cure other than delivery, preeclampsia is the leading cause of iatrogenic preterm birth. We show that preeclampsia shares pathophysiologic features with recognized protein misfolding disorders. These features include urine congophilia (affinity for the amyloidophilic dye Congo red), affinity for conformational state–dependent antibodies, and dysregulation of prototype proteolytic enzymes involved in amyloid precursor protein (APP) processing. Assessment of global protein misfolding load in pregnancy based on urine congophilia (Congo red dot test) carries diagnostic and prognostic potential for preeclampsia. We used conformational state–dependent antibodies to demonstrate the presence of generic supramolecular assemblies (prefibrillar oligomers and annular protofibrils), which vary in quantitative and qualitative representation with preeclampsia severity. In the first attempt to characterize the preeclampsia misfoldome, we report that the urine congophilic material includes proteoforms of ceruloplasmin, immunoglobulin free light chains, SERPINA1, albumin, interferon-inducible protein 6-16, and Alzheimer’s β-amyloid. The human placenta abundantly expresses APP along with prototype APP-processing enzymes, of which the α-secretase ADAM10, the β-secretases BACE1 and BACE2, and the γ-secretase presenilin-1 were all up-regulated in preeclampsia. The presence of β-amyloid aggregates in placentas of women with preeclampsia and fetal growth restriction further supports the notion that this condition should join the growing list of protein conformational disorders. If these aggregates play a pathophysiologic role, our findings may lead to treatment for preeclampsia.

scholarly journals Molecular alteration of the 140-megadalton plasmid associated with loss of virulence and Congo red binding activity in Shigella flexneri.

1986 ◽  
Vol 51 (2) ◽  
pp. 470-475 ◽  
Author(s):  
C Sasakawa ◽  
K Kamata ◽  
T Sakai ◽  
S Y Murayama ◽  
S Makino ◽  
...  
Keyword(s):  
Congo Red ◽  
Shigella Flexneri ◽  
Binding Activity ◽  
Molecular Alteration

Delivery of anticancer drugs via isolated hepatic perfusion: A promising strategy in the treatment of irresectable liver metastases?

1998 ◽  
Vol 14 (3) ◽  
pp. 262-268 ◽  
Author(s):  
Alexander L. Vahrmeijer ◽  
Marjolijn M. van der Eb ◽  
Jan Hein van Dierendonck ◽  
Peter J. K. Kuppen ◽  
Cornelis J. H. van de Velde
Keyword(s):  
Liver Metastases ◽  
Anticancer Drugs ◽  
Hepatic Perfusion ◽  
Promising Strategy ◽  
Isolated Hepatic Perfusion

PROTEINS IN TISSUE EXTRACTS WHICH BIND INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN-3 (IGFBP-3)

1995 ◽  
Vol 145 (1) ◽  
pp. R1-R6 ◽  
Author(s):  
S. Hodgkinson ◽  
P. Fowke ◽  
N. Al Somai ◽  
M. McQuoid
Keyword(s):  
Enzyme Inhibitors ◽  
Cellular Level ◽  
Binding Activity ◽  
Rat Tissues ◽  
Major Band ◽  
Structural Characterisation ◽  
Novel Proteins ◽  
Cell Membrane Binding ◽  
Triton X ◽  
Igfbp 3

ABSTRACT Membrane associated IGFBP-3 is now known to play a role in the modulation of IGF at the cellular level, but mechanisms involved in cell membrane binding are far from certain. In this study we report the identification and initial structural characterisation of proteins in a range of sheep and rat tissues which specifically bind recombinant human non-glycosylated IGFBP-3. Tissues were homogenised in Tris HCl (0.1 M, pH 7.4), containing proteolytic enzyme inhibitors and the residues re-extracted in buffer containing SDS and Triton X-100 (both 1% w/v) prior to analysis. These were subjected to SDS-PAGE, electro-blotted onto nitrocellulose and subjected to ligand blot analysis (LBA) using radioiodinated IGFBP-3 as ligand. LBA revealed a major band of binding activity migrating at 60 kDa in extracts of rat muscle while sheep muscle contained forms of 52 and 40 kDa as the principal species and ovine pancreatic extracts an abundance of the 40 kDa variant alone. Distribution of the binding activity appears tissue specific. Apart from skeletal muscle, pancreas and a small amount of the 52 kDa form in pituitary, analysis revealed no evidence of IGFBP-3 binding in a range of other sheep tissues including liver, kidney, spleen, intestine, adrenal, brain, mammary, uterus, ovary and plasma. The binding activity is TCA precipitable, trypsin digestible, dose responsive and relatively specific for IGFBP-3 since the related proteins recombinant human IGFBP-2 and purified caprine IGFBP-4 failed to bind. Additionally, IGFBP-3 binding to these species appeared unaffected by presaturation of IGFBP-3 with IGF-I, nor by their transient acidification which together with molecular weight estimates and their pattern of tissue distribution suggests they are not related to the acid labile subunit of the ternary 150 kDa IGFBP complex. IGFBP-3 binding and molecular mobility of the species were unaffected by sample reduction but binding was suppressed in a concentration dependent fashion by heparin. Finally LBA using 125I-Concanavalin A revealed the 40 kDa species to be glycosylated while the 52 kDa form was not. Functions of these novel proteins in targeting or modulating IGF activity at the cellular level remain to be clarified.

scholarly journals Thermoregulated expression of a cloned congo red binding activity gene ofShigella flexneri

1985 ◽  
Vol 28 (3) ◽  
pp. 281-286 ◽  
Author(s):  
Charles E. Chambers ◽  
Sharon L. Stockman ◽  
David W. Niesel
Keyword(s):  
Congo Red ◽  
Binding Activity

Development of inhibitors as research tools for carbohydrate-processing enzymes

2012 ◽  
Vol 40 (5) ◽  
pp. 913-928 ◽  
Author(s):  
Tracey M. Gloster
Keyword(s):  
Present Article ◽  
Enzyme Inhibitors ◽  
Structure And Function ◽  
Glycoside Hydrolases ◽  
Processing Enzymes ◽  
Cellular Processes ◽  
Domains Of Life ◽  
And Function ◽  
Complex Glycan ◽  
Synthesis And Degradation

Carbohydrates, which are present in all domains of life, play important roles in a host of cellular processes. These ubiquitous biomolecules form highly diverse and often complex glycan structures without the aid of a template. The carbohydrate structures are regulated solely by the location and specificity of the enzymes responsible for their synthesis and degradation. These enzymes, glycosyltransferases and glycoside hydrolases, need to be functionally well characterized in order to investigate the structure and function of glycans. The use of enzyme inhibitors, which target a particular enzyme, can significantly aid this understanding, and may also provide insights into therapeutic applications. The present article describes some of the approaches used to design and develop enzyme inhibitors as tools for investigating carbohydrate-processing enzymes.

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