Current Medicinal Chemistry (v.21, #30)
Targeting the Mannose Receptor with Mannosylated Subunit Vaccines by B. Sedaghat, R. Stephenson, I. Toth (3405-3418).
The mannose receptor (MR) is an important component of the immune system and understanding the structuraland conformational characteristics of this receptor is a key aspect of vaccine design. Improved understanding of the roleof carbohydrate recognition domains 4-7 (CRDs 4-7) in recognising glycosylated ligands present on the surface of pathogenssuch 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 knowledgeabout the MR structural properties. The MR was found to be an early responder in immunogenic pathways. Many attemptshave been made to mimic the structural properties of yeast mannan by attaching mannan or mannose to antigenicproteins or peptide epitopes. However, a more detailed understanding of the structural properties of the MR is necessaryfor the design of targeted vaccines. This review describes the structure of the MR and provides an overview of the use ofmannosylated proteins and peptides for vaccine targeting.
Effect of DNA Repair Deficiencies on the Cytotoxicity of Drugs Used in Cancer Therapy - A Review by Jose Manuel Calderon-Montano, Estefania Burgos-Moron, Manuel Luis Orta, Miguel Lopez-Lazaro (3419-3454).
Tumor cells often have defects in DNA repair pathways that make them vulnerable to specific DNA-damaginganticancer agents. The identification of DNA repair defects in tumor cells and the evaluation of their influence on the cytotoxicityof 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 repairpathways (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 FDAapprovedanticancer drugs. It is shown that specific deficiencies in these DNA repair pathways alter the cytotoxicity of 60anticancer drugs, including classical DNA-targeting drugs (e.g., alkylating agents, cytotoxic antibiotics, DNA topoisomeraseinhibitors and antimetabolites) and other drugs whose primary pharmacological target is not the DNA (e.g., antimitoticagents, hormonal and targeted therapies). This information may help predict response to anticancer drugs in patientswith tumors having specific DNA repair defects.
Body Mass Index, Lipid Metabolism and Estrogens: Their Impact on Coronary Heart Disease by G.D. Kolovou, V. Kolovou, P.M. Kostakou, S. Mavrogeni (3455-3465).
Estrogens influence lipid metabolism and body fat distribution in women. Premenopausal women have increasedlipoprotein lipase action in abdominal and femoral subcutaneous fat compared with men of the same age. Estrogensmay also affect adipose tissue either directly through specific estrogen receptors or indirectly via their effects onother tissues. As adipose tissue produces several cytokines including leptin, adiponectin and interleukin-6, estrogens mayalter their levels, thus influencing various biological processes. Lack of estrogens such as in menopause, causes an increasein visceral adiposity, leading to changes in lipid and lipoprotein metabolism. Due to those alterations, postmenopausalwomen 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.
Perspectives on Tuberculosis Pathogenesis and Discovery of Anti- Tubercular Drugs by Fidele Ntie-Kang, Joseph N. Yong, Luc C. Owono Owono, Wolfgang Sippl, Eugene Megnassan (3466-3477).
Based on the global burden of tuberculosis and resistant strains that have recently emerged, not responding toexisting therapies, it has become urgent to search for new remedies against this global human plague that has been compoundedby 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-TBdrug research, identifying some of the challenges being faced by researchers in the field and sheds light on possible waysforward, particularly in low-income countries.
Novel In Situ Activity Assays for the Quantitative Molecular Analysis of Neurodegenerative Processes in the Retina by P.A.R. Ekstrom, M. Ueffing, E. Zrenner, F. Paquet-Durand (3478-3493).
The mechanisms of neuronal cell death are still only poorly understood, which has hindered the advancementof therapies for many currently untreatable neurodegenerative diseases. This calls for the development of new methodswhich 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 biochemicalassays 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 assessedindirectly using in situ immunohistological techniques to detect PKG-activity-dependent products. Combining these assayswith in situ cell death markers revealed close temporospatial correlations, suggesting causal connections between thePKG, 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 matchby 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 inheritedretinal degeneration. Comparing different animal retinal degeneration models uncovered striking similarities in enzymaticactivities, suggesting a generality of the destructive pathways. Taken together, these findings provided a number of noveltargets for neuroprotection and as such opened up new perspectives for the therapy of hereditary neurodegeneration in theretina and possibly other parts of the central nervous system.
Effects of Tetrahydrohyperforin in Mouse Hippocampal Slices: Neuroprotection, Long-term Potentiation and TRPC Channels by C. Montecinos-Oliva, A. Schuller, J. Parodi, F. Melo, N.C. Inestrosa (3494-3506).
Tetrahydrohyperforin (IDN5706) is a semi-synthetic compound derived from hyperforin (IDN5522) and is themain active principle of St. John's Wort. IDN5706 has shown numerous beneficial effects when administered to wild-typeand double transgenic (APPswe/PSEN1 E9) mice that model Alzheimer's disease. However, its mechanism of action iscurrently unknown. Toward this end, we analysed field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampalslices incubated with IDN5706 and in the presence of the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG), theTRPC channel blocker SKF96365, and neurotoxic amyloid β-protein (Aβ) oligomers. To study spatial memory, Morriswater maze (MWM) behavioural tests were conducted on wild-type mice treated with IDN5706 and SKF96365. In silicostudies were conducted to predict a potential pharmacophore. IDN5706 and OAG had a similar stimulating effect onfEPSPs, 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 TRPC3/6/7channel subfamily. The unveiling of the drug's mechanism of action is a necessary step toward the clinical use ofIDN5706 in Alzheimer's disease.