Mini Reviews in Medicinal Chemistry - Volume 7, Issue 11, 2007

CXCR3 and CCR5 are chemokine receptor that are predominantly expressed on the surface of Th1 polarized T cells. In a variety of human and experimental autoimmune diseases the enhanced expression of CXCR3 and CCR5 binding chemokine ligands is followed by the recruitment of CXCR3- and CCR5-positive T cells, indicating an important role for these chemokine receptors in T cell-mediated tissue damage. In this review, we summarize a number of in vivo studies available on the neutralization of CXCR3 and CCR5 in inflammatory disease, and specifically focus on the potential therapeutic effects of CXCR3 and CCR5 blockade in human autoimmune disease and organ transplantation.

Quantitative structure-activity relationship (QSAR) and quantitative structure-property relationship (QSPR) models have been extensively used for predicting compounds of specific pharmacodynamic, pharmacokinetic, or toxicological property from structure-derived physicochemical and structural features. These models can be developed by using various regression methods including conventional approaches (multiple linear regression and partial least squares) and more recently explored genetic (genetic function approximation) and machine learning (k-nearest neighbour, neural networks, and support vector regression) approaches. This article describes the algorithms of these methods, evaluates their advantages and disadvantages, and discusses the application potential of the recently explored methods. Freely available online and commercial software for these regression methods and the areas of their applications are also presented.

Privileged structures are defined as molecular frameworks which are able of providing useful ligands for more than one type of receptor or enzyme target by judicious structural modifications. In the present work, we describe some examples and applications of the usefulness of the privileged structure concept for the structural design of new drug candidates, by discussing the eligibility of such motifs, including the identification of the N-acylhydrazone template as privileged structures.

Epidemiological studies have suggested a correlation between consumption of carotenoid-rich food and incidence of chronic diseases. In this review chemical structure, bioavailability and mechanisms of action of carotenoids most represented in human diet, mainly ß-carotene and lycopene, are reported, with focus on results obtained with cells in culture.

Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for gene regulation in glucose and lipid metabolism. It has been recently implicated that PPARs regulate cellular proliferation and inflammatory responses; some agonists for PPARs ameliorate experimental autoimmune encephalomyelitis, a model of multiple sclerosis (MS) in humans. This article will outline current experimental evidence suggesting potential clinical benefits for patients with MS.

The important roles of FoxP3+ T cells in many immunological or cancerous diseases are now well established. The research field is now moving in the direction to fine-control the generation, migration, expansion, and function of FoxP3+ cells in an effort to prevent and cure specific types of diseases. Potential molecular targets to regulate FoxP3+ T cells are reviewed in this article.

Histidine kinases are ubiquitous molecular sensors that are used by bacteria to detect and respond to a myriad of environmental signals. They are attractive antimicrobial targets because of their roles in mediating the virulence of pathogenic organisms, as well as the ability of bacteria to resist host defenses and develop resistance to antibiotics. In this review, we discuss the challenges involved in developing specific inhibitors of this highly diverse group of kinases.

Viruses can produce viral oncoproteins that drive multiple genetic alterations as the consequence of neoplastic transformation. Viral proteins encoded by onco-related viruses such as polyomavirus SV40 or Epstein-Barr virus are involved in cellular processes resulting in imbalance between proliferation and cell death, knowledge of which continues to be crucial for combating cancer. On the other hand, viruses also generate viral components that, from a cold viral protein, can become a tumor-selective killer by sensing cellular tumorigenic hallmarks. For instance, the avian virus derived apoptin protein has been proven to induce tumor-regression in various pre-clinical animal models without showing detectable side effects. In particular, apoptin-interacting protein partners such as components of the anaphase promoting complex were identified as potential anticancer drug targets. The adenovirus-derived protein E4orf4, another viral protein with tumor-specific apoptosis characteristics, has been proven to interact with the tumor-suppressor protein phosphatase 2A. This review aims to describe recent studies with representative viral elements that have contributed to our understanding of critical tumorigenic processes and have conferred an impact on the development of novel anti-cancer therapies.

RNA interference is a biological process that controls gene silencing in all living cells. Targeting the RNA interference system represents a novel therapeutic strategy able to intercede with multiple disease-related genes and to target many neurodegenerative diseases. Recently, the design of small interfering RNA-selective compounds has become more straightforward because of the significant progress made in predictive modeling for new therapeutic approaches. Although in vivo delivery of RNA interference remains a significant obstacle, new data show that RNAi blocks gene function in vivo, suggesting a potential therapeutic approach for humans. Some groups have demonstrated the efficacy of RNAi therapy in Alzheimer's disease. Results, based on animal models, show a down-regulation of the amyloid precursor protein and a consequent reduction of the amyloid-β peptide accumulation in the brain or the inactivation of β-secretase (BACE1). Indeed, lentiviral vectors expressing siRNAs targeting BACE1 reduce amyloid production and the neurodegenerative and behavioural deficit in APP transgenic mice. This review highlights recent advances in RNA research and focuses on strengths and weaknesses of RNAi compounds in Alzheimer's disease.

One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for isoniazid, rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms.