Mini Reviews in Medicinal Chemistry - Volume 9, Issue 8, 2009

Despite the considerable progress in antiretroviral therapy, the eradication of HIV-1 remains unfeasible. Therefore, novel agents are under investigation. The aim of this review is to summarize the conventional compounds, to describe the recently approved agents, and to take a comprehensive look at the clinically relevant findings of current research.

Paraoxonase-1 is a lactonase and an esterase and it plays a protective role in toxicity as well as in diseases involving oxidative stress. Recently, insights into how it may be modulated by environmental factors have acquired clinical relevance. This article reviews the state-of-the-art evidence regarding PON1 modulation by pharmacological products as well as nutritional and lifestyle factors.

Epigenetic modifications include DNA methylation, histone modifications, and noncoding RNAs containing microRNAs (miRNA). miRNAs are small noncoding RNAs that are 21 to 25 nt in length; they downregulate gene expression during cell development, cell proliferation, cell differentiation, and apoptosis. They play a critical role in human carcinogenesis. Presently, evidences show that miRNAs participate as oncogenic miRNAs or tumor suppressors in the developmental and physiological processes of human colorectal cancer (CRC). Disturbed miRNA expression may be attributable to a mechanism involving multiple factors. In this review, we focus on the colorectal miRNA expression profile and further discuss the miRNA regulatory network involved in the tumorigenesis of human CRC. We, thus, hope to open up new avenues for anticancer therapy based on the epigenetic regulation of miRNA.

It has recently been demonstrated that short RNA molecules, called microRNAs, are one of the major factors regulating the expression of human genes. There are several lines of evidence that microRNAs also play a key role in host-virus interactions. It is believed that both human- and virus-encoded miRNA will, in the nearest future, become very attractive targets of antiviral therapy.

Antibiotics currently under study by the Food and Drugs Administration include: faropenem (for treatment of sinusitis, bronchitis, and community-acquired pneumonia), dalbavancin (for catheter infections), telavancin (for treatment of nosocomial pneumonia), oritavancin (for bacteremia), ceftobiprole and iclaprim (for pneumonias). Moreover, all of them would be useful for skin and soft tissue infections.

To be an effective medicine a drug has to possess many attributes to ensure target potency and specificity, lack of toxicity, bioavailability and duration of action. Discovering a compound with these properties is invariably an evolutionary process. Fragment based drug discovery sets out to identify a starting compound by screening a library of small molecules representing fragments which cover the chemical space of drug like matter. Fragment based screening is increasingly used in the pharmaceutical industry in the early stages of lead identification and optimization. We will provide an introduction into this approach and discuss a number of examples which show how fragment based drug discovery has been used in the discovery of starting points for drug discovery programs and in their optimization.

Human villous trophoblast differentiation is a complex and highly regulated process essential for the well-being of the pregnancy and fetal development. In this review, we present an overview of the role of MAPKs signalling in morphological and functional differentiation of villous trophoblast.

Photodynamic activity of chemical compounds towards microorganisms was first published at the turn of 20th century and it is based on the concept that a chemical compound, known as the photosensitizer, is localized preferentially in the microorganism and subsequently activated by low doses of visible light of an appropriate wavelength to generate reactive oxygen species that are toxic to the target microorganisms. Processes, in which absorption of light by a photosensitizer induces chemical changes in another molecule, are defined as photosensitizing reactions. Since the middle of the last century, antibacterial photosensitizing reactions were forgotten because of the discovery and the beginning of the Golden Age of antibiotics. Certainly, in the last decades the worldwide rise in antibiotic resistance has driven research to the development of new anti-microbial strategies. Different classes of molecules including phenothiazine, porphyrines, phthalocyanines, and fullerenes have demonstrated antimicrobial efficacy against a broad spectrum of antibiotic resistant microorganisms upon illumination. Due to their extended pi-conjugated system these molecules absorb visible light, have a high triplet quantum yield and can generate reactive oxygen species upon illumination. This mini-review will focus on some major advances regarding physical and chemical properties of photosensitizers and light sources that appear to be suitable in the field of antimicrobial photodynamic therapy. Currently, topical application of a photosensitizer on infected tissues and subsequent illumination seems to be the most promising feature of antimicrobial photodynamic therapy, thereby not harming the surrounding tissue or disturbing the residual bacteria-flora of the tissue.

A concise account of the physicochemical properties of morphine and its derivatives of therapeutic interest is provided. Such properties include macroscopic and microscopic acid/base parameters, lipophilicity, solubility, permeability that all influence the fate of drugs in the body. The dependence of these parameters on pH is discussed and subsequent implications in drug administration and formulation are presented.

Some natural triterpenes exert a definite antiviral activity on several human viruses. New synthetic derivatives of glycyrrhizic acid (GL) are even more active than the parental molecule. GL can alter the expression of viral genes involved in cell transformation, thus opening a new window for speculating on viral cancerogenesis.

Amyloid-beta-peptide (Aβ) binding to mitochondrial Aβ-binding alcohol dehydrogenase (ABAD) enzyme triggers a series of events leading to mitochondrial dysfunction characteristic of Alzheimer's disease (AD). Thus this interaction may represent a novel target for treatment strategy against AD. In this review we summarize current findings regarding the ABAD-Aβ interaction, namely structural and biophysical data, available inhibitors and more recent data from proteomic studies.

The present paper reviews and discusses selectivity of ABCC4 (MRP4), ABCC5 (MRP5) and ABCC11 (MRP8) as cellular efflux pumps for cAMP and cGMP. These transporters are potential drug targets for selective modulation of cyclic nucleotide action.

There is an urgent need for the design and development of new and safer drugs for the treatment of human immunodeficiency virus (HIV) infection, specifically active against drug-resistant viral strains. Recently, sulfanyltriazole/ tetrazole derivatives were reported as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), with low nanomolar intrinsic activity against RT and submicromolar antiviral activity in HIV infected cells. In this review, the structural modifications, SAR analysis and docking studies of sulfanyltriazole/tetrazoles HIV-1 NNRTIs are discussed, and other interesting NNRTIs with the same or similar pharmacophore as the sulfanyltriazole/tetrazole derivatives are also presented and analyzed for their in SAR.