Current Medicinal Chemistry - Volume 21, Issue 30, 2014

The mannose receptor (MR) is an important component of the immune system and understanding the structural and conformational characteristics of this receptor is a key aspect of vaccine design. Improved understanding of the role of carbohydrate recognition domains 4-7 (CRDs 4-7) in recognising glycosylated ligands present on the surface of pathogens such as C.albicans, P. carinii, L. donovani, and M. tuberculosis has given new insight into MR vaccine development. Initial studies identified mannan and its derivatives to be important ligands in MR targeting, providing essential knowledge about the MR structural properties. The MR was found to be an early responder in immunogenic pathways. Many attempts have been made to mimic the structural properties of yeast mannan by attaching mannan or mannose to antigenic proteins or peptide epitopes. However, a more detailed understanding of the structural properties of the MR is necessary for the design of targeted vaccines. This review describes the structure of the MR and provides an overview of the use of mannosylated proteins and peptides for vaccine targeting.

Tumor cells often have defects in DNA repair pathways that make them vulnerable to specific DNA-damaging anticancer agents. The identification of DNA repair defects in tumor cells and the evaluation of their influence on the cytotoxicity of anticancer drugs are active areas of scientific investigation that may help rationalize and improve cancer chemotherapy. This article reviews the available data on the influence of defects in proteins involved in the major DNA repair pathways (i.e., homologous recombination, non-homologous end joining, base excision repair, nucleotide excision repair, mismatch repair, Fanconi anemia repair, translesion synthesis and direct reversal repair) on the cytotoxicity of the FDAapproved anticancer drugs. It is shown that specific deficiencies in these DNA repair pathways alter the cytotoxicity of 60 anticancer drugs, including classical DNA-targeting drugs (e.g., alkylating agents, cytotoxic antibiotics, DNA topoisomerase inhibitors and antimetabolites) and other drugs whose primary pharmacological target is not the DNA (e.g., antimitotic agents, hormonal and targeted therapies). This information may help predict response to anticancer drugs in patients with tumors having specific DNA repair defects.

Estrogens influence lipid metabolism and body fat distribution in women. Premenopausal women have increased lipoprotein lipase action in abdominal and femoral subcutaneous fat compared with men of the same age. Estrogens may also affect adipose tissue either directly through specific estrogen receptors or indirectly via their effects on other tissues. As adipose tissue produces several cytokines including leptin, adiponectin and interleukin-6, estrogens may alter their levels, thus influencing various biological processes. Lack of estrogens such as in menopause, causes an increase in visceral adiposity, leading to changes in lipid and lipoprotein metabolism. Due to those alterations, postmenopausal women are more prone to coronary heart disease. In this review the influence of estrogens on body mass index, lipid metabolism and some of the therapeutic options will be analyzed.

Based on the global burden of tuberculosis and resistant strains that have recently emerged, not responding to existing therapies, it has become urgent to search for new remedies against this global human plague that has been compounded by HIV co-infection. Thus, the search for new drugs against the disease-causing agent, Mycobacterium tuberculosis (MTB), is an ongoing effort. This review discusses the state-of-the-art in anti-tuberculosis pathogenesis and anti-TB drug research, identifying some of the challenges being faced by researchers in the field and sheds light on possible ways forward, particularly in low-income countries.

The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancement of therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methods which reveal critical molecular mechanisms of the celldeath machinery with both high sensitivity and cellular resolution. Using animal models for hereditary neurodegeneration in the retina, we have developed or adapted different biochemical assays to determine the enzymatic activities of calpain, poly-ADP-ribose-polymerase (PARP), and histone deacetylase (HDAC) directly and in situ. Additionally, the enzymatic activity of cGMP-dependent protein kinase (PKG) was assessed indirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assays with in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between the PKG, HDAC, PARP and calpain activities and neuronal cell death. Using different pharmacological and genetic manipulations, causality could indeed be demonstrated. Surprisingly, the often dramatic rises in metabolic activities didnot match by corresponding increases in expression, highlighting the importance of analyses of protein activities at the cellular level. The above mentioned studies identified a number of metabolic processes previously unknownto be involved in inherited retinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymatic activities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of novel targets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in the retina and possibly other parts of the central nervous system.

Tetrahydrohyperforin (IDN5706) is a semi-synthetic compound derived from hyperforin (IDN5522) and is the main active principle of St. John’s Wort. IDN5706 has shown numerous beneficial effects when administered to wild-type and double transgenic (APPswe/PSEN1ΔE9) mice that model Alzheimer’s disease. However, its mechanism of action is currently unknown. Toward this end, we analysed field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices incubated with IDN5706 and in the presence of the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG), the TRPC channel blocker SKF96365, and neurotoxic amyloid β-protein (Aβ) oligomers. To study spatial memory, Morris water maze (MWM) behavioural tests were conducted on wild-type mice treated with IDN5706 and SKF96365. In silico studies were conducted to predict a potential pharmacophore. IDN5706 and OAG had a similar stimulating effect on fEPSPs, which was inhibited by SKF96365. IDN5706 protected from reduced fEPSPs induced by Aβ oligomers. IDN5706 improved spatial memory in wild-type mice, an effect that was counteracted by co-administration of SKF96365. Our in silico studies suggest strong pharmacophore similarity of IDN5706 and other reported TRPC6 activators (IDN5522, OAG and Hyp9). We propose that the effect of IDN5706 is mediated through activation of the TRPC3/6/7 channel subfamily. The unveiling of the drug’s mechanism of action is a necessary step toward the clinical use of IDN5706 in Alzheimer’s disease.