Letters in Drug Design & Discovery - Volume 4, Issue 1, 2007

A high throughput screen was conducted to identify inhibitors of the RNA-dependent RNA polymerase (RdRp) of HCV. One of the classes identified was related to toxoflavin, a naturally occurring antibiotic. These compounds were potent inhibitors of HCV RdRp, with optimization of the initial hits giving compounds with half-maximal inhibition at 200 nM. However, binding studies indicated that a physical interaction with RdRp was too weak to be detected. Inhibition was dependent on reducing agent, implicating the flavin core as essential to the inhibitory properties of these compounds. The accumulation of the inhibitory species occurred over a time span of 1 to 2 hours, the period of time required for oxidation of a 10 to 100-fold excess of DTT by the flavin. These results indicate that the inhibitory species is likely to be a chemically reactive species resulting from the interaction of the flavin and DTT. Human RNA polymerase II was also sensitive to inhibition by these toxoflavin-like compounds. While this class of inhibitors has generated interest as antibacterial, antifungal and antitumor agents, their use has been limited by toxicity. These results provide a potential mechanism to explain the toxicity of these compounds.

The Na+-HCO3 - symport plays as significant role as the Na+/H+ exchanger in ischemia/reperfusion injury. Under bicarbonate free conditions, however, the Na+-HCO3 - symport does not work, and so the protective efficacy of Na+/H+ exchanger inhibitors is overestimated. We discuss the reasons for the inconsistencies in studies of the Na+/H+ exchanger.

In this paper, a preliminary structure-based virtual screening study was developed, using AUTODOCK 3.0 program and our previously published CB2 receptor model, in order to further evaluate its reliability. Starting from the Maybridge database, four compounds were tested for their CB2 affinity and three of them showed Ki values of 7.8-8.0 μM. The results obtained confirmed the reliability of the CB2 receptor model, encouraging the application of larger virtual screening studies, and furthermore the three screened ligands could be used as interesting leads for the development of new active CB2 ligands.

The interaction between the chemokine, CXCL12 and its receptor, CXCR4 is known to be involved in several intractable disease processes, including HIV infection, cancer cell metastasis, leukemia cell progression and rheumatoid arthritis. It is conjectured that this interaction may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. This article describes the development in our laboratory of a number of specific CXCR4 antagonists.

The design, synthesis and evaluation of several dual PPARα/γ agonists with three different heterocycles, viz. pyrazolo[4,3-d]pyrimidin-7-one, quinazolin-4-one and benzo[e][1,3]oxazine-4-one for the treatment of type 2 diabetes and associated dyslipidemia are described. Among them, compound 5cb was found to possess a potent dual PPARα/β agonist property. It significantly reversed diabetic hyperglycemia while improving overall lipid homeostasis in preclinical animal models.

Cystine knot microproteins are promising novel scaffolds for the oral delivery of pharmacophoric sequences. In order to cross mucosal membranes, these scaffolds should be stable towards membrane bound enzymes (MBE) of the intestinal mucosa. Therefore, two novel cystine-knot microprotein scaffolds have been evaluated regarding their stability towards MBE of excised rat small intestine and the most abundant membrane bound exopeptidase aminopeptidase N. It was shown, that SE-ET-TP-020 (37 amino acids) is degraded by membrane bound enzymes of rat intestinal mucosa, whereas SE-MC-TR-020 (32 amino acids) is not degraded by these enzymes. Neither of the two evaluated scaffolds was degraded by aminopeptidase N. The results of this study further support the hypothesis that scaffolds with 37 amino acids are more susceptible towards MBE caused degradation in comparison to scaffolds with about 30 amino acids.

Distamycin nitrogen mustard derivatives with different substituents at the amidino moiety located at the C-terminal of the peptide were synthesized. The in vitro antitumor activity was determined against human chronic leukemia K562 cells. Compound 3, bearing a terminal ethylamido group, had the best antitumor activity with an IC50 value of 0.72 μM. Compound 5, bearing a terminal dimethylamino group, had an IC50 value of 2.0 μM. This result suggests that a terminal positive charge is not essential for optimal antitumor activity.

For the last several years, the drug industry primarily has relied on drugs that target a single gene or enzyme in a pathway involved in disease progression with the idea that such a drug will have minimum side effects and maximal efficacy. Recent observations, however, indicate that a drug that targets multiple genes/enzymes involved in several pathways, thus exhibiting promiscuity, is often more efficacious with less side effects. Thus significant efforts are being made to use our understanding in pharmacogenomics and structural biology to design polypharmacological drugs that are able to act at multiple sites. Recent studies with pathogenic bacteria demonstrate that such bacteria produce water-soluble, low molecular weight redox proteins that appear to act as weapons against various invaders, internal or external, of human body that cause diseases such as cancers, malaria or AIDS. The potential of finding such promiscuous lipophilic bacterial proteins active against multiple diseases may lead in the future to an antibiotic-like industry targeted towards non-prokaryotic agents of human diseases.

Sirtuins are enzymes that deacetylate proteins at the expense of NAD. The nuclear forms of sirtuins have generated an enormous amount of interest due to their putative regulation of lifespan. Yeast sirtuins and human sirtuins are involved in very different biochemical processes that make extrapolation of yeast results to the human situation difficult. This review critically examines the issues of NAD biochemistry in relation to nuclear sirtuin activity. Putative sirtuin inhibitors and activators are discussed, especially in terms of lifespan extension by sirtuin activators.

A series of (E) 2-quinolinylmethylidene-5,7-dimethoxyindanones were prepared via base catalyzed Claisen-Schmidt condensation of 5,7-dimethoxy-1-indanone with the appropriate 2-chloro-3-formylquinoline derivative. Evaluation of their in vitro inhibition of β-hematin formation and hemoglobin hydrolysis and in vivo efficacy in rodent Plasmodium berghei suggest the antimalarial activity is derived from inhibition of hemoglobinolytic proteases.

This review summarizes our investigations on the reactivity of human polymorphonuclear neutrophils treated with the pharmacologically active compounds that liberate nitric oxide in vitro. The results of our study show that nitric oxide liberation from sodium nitroprusside (SNP), 3- morpholinosydnonimine (SIN-1) and Diethylamine/NO is a time-and dose-dependent and the kinetics of NO production is different between the three compounds. The effect of exogenously administered compounds on the neutrophil functional state depends on the compounds concentration, rate and mechanism of NO liberation, treatment time of neutrophils and on the stimulus employed to cells activation. SNP and DEA/NO actions on neutrophil respiratory burst are mainly associated with modulation of PKC and MEK1/2 activities, while SIN-1 with PKTs activities. The course of neutrophil apoptosis in vitro shows that different compounds depending on the mechanisms of NO release exert differential effects on apoptotic events. SNP and SIN-1 are involved in the process of bacterial killing by neutrophils. We conclude that NO released and its derivatives formed in the course of the interaction between neutrophils and bacteria are responsible for the enhancement of neutrophil antibacterial activity.

The antiparasitic and antifungal activities of nine amphibian skin secretions were studied in different in vitro models. Seven secretions presented a considerable antiprotozoan activity and one showed promising results against Candida sp. These results can be the basis for the development of new drugs, especially for neglected parasitic diseases.

New ultrasound contrast agents that incorporate a therapeutic compound have become of interest. Such an ultrasound contrast agent particle might act as the vehicle to carry a drug or gene load to a perfused region of interest. The load could be released with the assistance of ultrasound. Generally, an increase in shell thickness increases the acoustic amplitude needed to disrupt a bubble. High acoustic amplitudes, however, have been associated with unwanted effects on cells. It would be interesting to incorporate a droplet containing drugs or genes inside a microbubble carrier. A liquid core surrounded by a gas encapsulation has been referred to as antibubble. In this paper, the creation of an antibubble with the aid of ultrasound has been demonstrated with high-speed photography.

A sol-gel and a freeze-casting process are used to produce tablet-like bodies without the standard compression. The advantage is that temperature sensible materials can be produced in tablet-like forms, thus other cost intensive production processes like capsulation or freeze drying are avoided. Different ways are introduced to characterize the suspension and the tablet. Herewith the influences of parameters like composition of the materials or freezing conditions on the final products should be clarified.