Letters in Drug Design & Discovery - Volume 2, Issue 2, 2005

We demonstrated that the uracil-DNA glycosylase inhibitor, when delivered to human melanoma cells using protein transduction technology, resulted in a dose and time dependent inhibition of uracil-DNA glycosylase (UNG) and this inhibited cell proliferation. These results suggest that a novel class of inhibitors specifically targeting UNG can be developed as potential anti-cancer agents.

The most common feature of human cancer cells is aneuploidy and a defective mitotic checkpoint is thought to be responsible. Since a group of anticancer drugs target the mitotic checkpoint, this review will discuss the association of mitotic checkpoint with chemotherapeutic drug sensitivity and suggest a novel therapeutic tool to achieve chemosensitization in human cancer cells.

Animal and human studies have shown angiotensin converting enzyme (ACE) inhibitors to be protective agents against myocardial injury, especially ischemia/reperfusion injury. In this review of the application of ACE inhibitors in heart surgery, I examine the problems involved and discuss their solutions.

New inhibitors of the ß-site amyloid precursor protein cleaving enzyme (BACE-1) are described. The hydroxyethyl transition state isostere of GT1017 has been replaced by the hydroxyethylamine (HEA), the hydroxyethylsulfide or the hydroxyethylurea groups. Biological evaluation has shown that the HEA analogue, obtained as epimeric mixture, inhibited BACE-1 with an IC50=0.12μM. Stereoselective synthesis showed s Read More

The analysis of the S3 binding region of the Hepatitis C Virus NS3 serine protease allowed replacing the P3 amino acid of a-ketoacid tripeptide inhibitors with an amphiphilic capping group. The binding mode of α-ketoacid (8) (IC50 = 1 μM) and the role of the amphiphilic group in non-covalent phenethylamide inhibitor (15) (IC50 = 21 μM) will be discussed.

We describe herein tetrapeptidyl α-ketoamide 4A based systematic P1 modifications alone or/and in combination with further P1; variations. These SAR efforts led to the discovery of a number of potent and selective HCV NS3 protease inhibitors such as 4B, 9, and 12 endowed with impressive cellular activity as measured in the replicon assay and very good therapeutic indexes. On the basis of its overall profile, compound 4B (V Read More

Chicken avidin is used in a wide variety of applications in the life sciences, due to its extraordinarily strong affinity for biotin. Avidin-biotin strategy has also recently established a role in medical targeting approaches for cancer treatments. An interesting new exploitation for avidin-biotin techniques is the utilization of this strong affinity in gene therapy, to target and enhance gene delivery to the appropriate target cells an Read More

Cordycepin (3;-deoxyadenosine) is a potent anti-leukemic, anti-fungal, and anti-parasitic nucleoside antibiotic. Unfortunately, the biological activity of cordycepin is attenuated by its rapid conversion to 3;-deoxyinosine by adenosine deaminase (ADA). We have synthesized a series of ADA-resistant N-aminal and N-thioaminal cordycepin derivatives, which are protected from inactivation by deamination and yet retain biologi Read More

A competitive dialysis method has been developed to screen compounds for their DNA binding properties, and it is based on directly comparing the binding of polyamide molecules to a series of distinctively varied, short, synthetic deoxyribonucleotides. Relative binding ratios for each polyamideoligonucleotide pairing were calculated from the concentrations of free polyamide and total polyamide in order to quantitativ Read More

Minocycline, the 7-dimethylamino- 6-dimethyl-desoxytetracycline hydrochloride, is a caspase-1 inhibitor and may serve as anti-apoptotic agent, thereby acting neuroprotective. It directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways, and decreases inducible nitric oxide synthetase activity. Minocycline delays disease progression in the transgenic mouse model of Huntington;s disease Read More

Human cytomegalovirus (HCMV) retinitis treated with frequent intraocular injections of ganciclovir is associated with complications such as endophthalmitis, retinal detachment and vitreous haemorrhage. Several formulations of biodegradable injectable PLGA microspheres with ganciclovir have been previously investigated as a possible alternative for treatment of HCMV retinitis. This report describes two new for Read More

Chronic hepatitis C is a ubiquitous disease, affecting approximately 170 million globally. The hepatitis C virus (HCV) is spread by parenteral transmission of body fluids, primarily blood or blood products. The hepatitis C viral genome is a positive-sense, single-stranded RNA molecule approximately 9.4kb in length, which encodes a polyprotein of about 3100 amino acids. There are 6 main genotypes of HCV, with each f Read More

Amidine-containing derivatives of the diphenylurea antimalarial lead compound WR268961, a putative plasmepsin inhibitor, were prepared and tested against erythrocyte-stage P. falciparum. Diamidine 8 was the most active compound, displaying IC50 values of 54 nM and 41 nM versus chloroquine sensitive (D6) and chloroquine resistant (W2) parasites, respectively.

To determine whether topically applied biologically active drugs can be used to protect the human immune system from sunlight, we studied the effect of tamarind xyloglucan polysaccharide, a natural and common fruit constituent, on solar-simulated, ultraviolet radiation-induced local immunosuppression and erythema in humans. Immunosuppression was studied in humans using a nickel contact hypersensitivity recall Read More