Current Enzyme Inhibition - Volume 9, Issue 2, 2013

Introduction: PAI-1 is a potent fibrosis promoting glycoprotein in a tissue dependent manner. We previously displayed that tacrolimus (FK506) toxicity increases vacuolar degeneration and arterial hyalinosis in cardiovascular tissue. FK506 toxicity induced transforming growth factor (TGF-β) expression. Renin angiotensin system (RAS) blockade partially reversed histopathological changes associated with FK506 toxicity. In the same model, we investigated the effects of FK506 and RAS blockade on PAI-1 expression. Materials and Methods: We examined cardiac expression of PAI-1 in a chronic FK506 toxicity model in Wistar rats. Study animals were divided into 4 groups. FK506 group was treated with FK506 intraperitoneally, FK506+Quinapril and FK506+Valsartan groups were treated Quinapril or Valsartan orally in addition to FK506. Control group was treated with saline. Immunohistochemical staining of cardiovascular tissue was semiquantitatively scored for PAI-1 expression. Results: FK506 significantly induced PAI-1 expression in the cardiovascular tissue compared to the control group (semiquantitative scores were 25±5 versus (vs) 49±21, p =0.01). Adding renin angiotensin system blockade with an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to FK506 increased FK506 induced PAI-1 expression. Semiquantitative PAI-1 expression scores were 49±21, 87±14 and 95±10 for FK506, FK506+ACEI, and FK506+ARB groups respectively (p<0.01). Conclusion: FK506 toxicity is associated with up-regulation of PAI-1 expression at the tissue level which is not attenuated after RAS blockade. These observations suggest that FK506 induces an angiotensin II independent increase on PAI-1 expression in cardiac tissue and/or elevated TGF-β and reduced BMP-7 levels with FK506 toxicity may reverse the inhibitory effects of RAS blockade on PAI-1 expression.

Lipoxygenases (LOs) include several members and constitute a family of dioxygenases containing one nonheme iron atom per molecule, which oscillates between Fe2+ (inactive enzyme) and Fe3+ (active form) during the catalytic cycle. They catalyze the oxygenation of polyunsaturated fatty acids containing a (1Z, 4Z)-penta-1, 4-diene system to the corresponding hydroxyperoxy derivatives. Although the cyclooxygenases could be considered specialized in the arachidonate pathway, the detailed mechanism of the LO reaction still remains controversial. It has been found that LOs are implicated in several processes such as cell differentiation, inflammation and carcinogenesis. Development of drugs that interfere with the formation or effects of these metabolites would be important for the treatment of various diseases like asthma, psoriasis, ulcerative colitis, rheumatoid arthritis, atherosclerosis, cancer and blood vessel disorders. Till now, asthma consists of the only pathological case in which improvement has been shown by LO inhibitors. Thus, the research has been directed towards the development of drugs that interfere with the formation of leukotrienes. In this review we will update the research efforts within the LOs inhibition and we will present recent findings, of LO inhibitors.

Phosphodiesterases (PDEs) are responsible for the hydrolysis of cyclic nucleotides (cAMP and c-GMP). Cyclic nucleotides are important intracellular secondary messengers in cell function, relaying the signals from hormones at specific cell-surface receptors. An increase of cAMP due to the stimulation of adenylyl cyclase or the inhibition of PDEs affects the activity of immune system and inflammatory cells. Thus, PDE4, a cAMP specific PDE, received much attention as a target for the treatment of the diseases like asthma and Chronic Obstructive Pulmonary Disease (COPD). Pyrazolo[4,3-c]quinoline-3-one nucleus has attracted considerable attention recently as PDE4 receptor antagonists which have shown remarkable therapeutic potential in the treatment of asthma and Chronic Obstructive Pulmonary Disease (COPD). In the present study, three dimensional quantitative structure activity relationship (3D QSAR) approach using CoMFA and CoMSIA was applied to a series of 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-ones as PDE4 receptor antagonists. For the purpose, 22 compounds from the series were used to develop and validate models. The robustness of the model was confirmed with the help of leave one out cross-validation method, while the predictive ability of models was tested using a test set containing three molecules. Novel compounds were designed on the basis of results of CoMFA and CoMSIA studies. Designed compounds were evaluated by Docking and Lipinski filters. 3D-QSAR models with high squared correlation coefficient of up to 0.9590 for CoMFA and 0.9740 for CoMSIA were established. Robustness of the models is demonstrated by R2 cv values of up to 0.8600 and 0.8230 for CoMFA and CoMSIA, respectively. Predictive ability of the models is reflected by R2 pred values of 0.865 and 0.926 for CoMFA and CoMSIA respectively. Predicted activity of the designed molecules correlated well with the docking scores and the molecules also passed the Lipinski filters. Developed models highlighted the importance of steric, electrostatic and hydrophobic properties of the molecules for PDE 4 receptor affinity. The designed compounds may serve as lead for the development of newer PDE4 inhibitors based on the 2, 5-dihydropyrazolo [4, 3-c] quinoline-3-one scaffold.

Nitric oxide synthase (NOS) is a dimeric enzyme that catalyses the production of nitric oxide (NO) in the human body. The nitric oxide has been identified as the most interesting and vital mediators for normal and pathological processes, including the regulation of blood pressure, neurotransmission, and macrophage defence system, but the over production of it can be toxic, hence their inhibitors are desired. In this article, the various isoforms of NOS and their roles are described and a detail of the development of their inhibitors has been presented. The inhibitors studied include aminopyridines, iminopiperidines, N-phenylamidines, benzoxazolones, isothioureas, oxazepanes, thiazepanes, diazepanes, 4,5-disubstituted-1,3-oxazolidin-2-imine derivatives, thiazolidines, pyrazoles, pyrazolines, and some others.

Fungal infections afflict an increasing number of patients due to increases in susceptible immunosuppressed populations such as those receiving chemotherapy, transplant conditioning or infections such as HIV. Poor responses to available therapy have prompted searches for novel drug targets, but screens can be difficult as expression of these targets often relies on specific inducing conditions present within the mammalian host. Cryptococcus is a yeast-like basidiomycete fungus capable of causing fatal cryptococcocis in both immunocompetent and immunocompromised individuals, and is currently the fourth cause of infectious death in regions of Sub-Sahara Africa, excluding HIV. A key virulence factor of Cryptococcus is a cell-wall laccase, which produces melanin in the presence of exogenous catecholamines. Screening melanin-deficient strains of the fungus is facile and has identified cellular processes critical for virulence including copper homeostasis and autophagy. As demonstrated here through the analysis of laccase regulatory networks of Cryptococcus, genetic analysis targeting virulence-associated regulatory pathways can lead to the discovery of promising novel drug candidates against fungal species.

The uptake and utilization of glucose and glutamine by cancer cells are markedly higher than by most nontransformed, normal epithelial and mesenchymal cells. This metabolic shift enables the production of ATP and anabolic precursors necessary for the synthesis of proteins, lipids and nucleotides required for survival, proliferation and invasiveness. The observations that certain oncogenic proteins (Ras, c-Myc and HIF-1α) and tumor suppressors (p53, PTEN, Rb and VHL) regulate the expression and activity of several metabolic enzymes have supported their potential as molecular targets for the development of anti-neoplastic agents. Indeed, recent pre-clinical studies have shown that several established and novel inhibitors of metabolic enzymes exhibit reasonable therapeutic indices when tested in xenograft models of tumorigenesis. In this review, we will discuss the rationale of targeting metabolic enzymes for the treatment of cancer and then will describe published pre-clinical and clinical data for several inhibitors of metabolism in cancer.

When extensive, fibrosis can impair the function of an affected organ. Despite a greater understanding of the causes and processes leading to organ fibrosis, there are a limited number of treatment options with minimal data supporting their utility. Identifying compounds for clinical use that inhibit fibrosis is an active area of investigation. In recent years, evidence for the utility of targeting the ubiquitin-proteasome system (UPS) in the inhibition of fibrosis has grown. Here we review the evidence for the interaction of the UPS with processes driving organ fibrosis, including the transforming growth factor beta pathway. We will also discuss the potential utility and harm of proteasome inhibition in the treatment of organ fibrosis.