Current Medicinal Chemistry (v.21, #3)

An Update on Autoinflammatory Diseases by F. Ciccarelli, M. De Martinis, L. Ginaldi (261-269).
Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized byrecurrent inflammatory episodes. From apathogenetic point of view they are determined by a dys regulation of innate immunity,without involvement of specific immunity (auto reactive T cells and auto antibodies). Recently, the increasedknowledge in the field of auto inflammation highlighted shared immune mechanisms in the pathogenesis of both classicalmonogenetic and multifactorial auto inflammatory diseases and a broad spectrum of chronic age-related inflammatory pathologies.The current increase in the prevalence of chronic inflammatory diseases makes this subject of topical interest.In the light of these considerations, we propose an update of auto inflammatory diseases and a new interpretation of autoinflammation with both theoretical and clinical implications.

Cobra Cardiotoxins: Membrane Interactions and Pharmacological Potential by P. V. Dubovskii, A. G. Konshina, R. G. Efremov (270-287).
Natural polycationic membrane-active peptides typically lack disulfide bonds and exhibit fusion, cellpenetrating,antimicrobial activities. They are mostly unordered in solution, but adopt a helical structure, when bound tophospholipid membranes. Structurally different are cardiotoxins (or cytotoxins, Ts) from cobra venom. They are fully β -structured molecules, characterized by the three-finger fold (TFF). Affinity of CTs to lipid bilayer was shown to dependon amino acid sequence in the tips of the three loops. In the present review, CT-membrane interactions are analyzedthrough the prism of data on binding of the toxins to phospholipid liposomes and detergent micelles, as well as their structuraland computational studies in membrane mimicking environments. We assess different hydrophobicity scales to comparemembrane partitioning of various CTs and their membrane effects. A comparison of hydrophobic/hydrophilic propertiesof CTs and linear polycationic peptides provides a key to their biological activity and creates a fundamental basis forrational design of new membrane-interacting compounds, including new promising drugs. For instance, from the viewpointof the data obtained on model lipid membranes, cytotoxic activity of CTs against cancer cells is discussed.

New Fabrication and Applications of Carbohydrate Arrays by Gangliang Huang, Xin Chen, Feng Xiao (288-295).
Carbohydrate arrays are used as high-throughput screening platforms to study the carbohydrate-mediated recognitionevents for glycobiology. The polysaccharide arrays are easy to fabricate by non-covalently or covalentlyimmobilizing polysaccharides onto array surfaces because polysaccharides have hydrophobic interactions.Oligosaccharides must be derived and covalently or non-covalently immobilized onto array surfaces to fabricateoligosaccharide arrays because they have hydrophilic interactions. At the moment, carbohydrate arrays are mainly used tostudy the carbohydrate-protein interactions and carbohydrate-binding lectins or antibodies, which are possible to beapplied to clinics and diagnoses. This review mainly summed up the new fabrication strategies of carbohydrate arrays andtheir applications in recent four years.

Clinically significant antibiotic resistance is one of the greatest challenges of the twenty-first century. Yet newantibiotics are currently being developed at a much slower pace than our growing need for such drugs. Instead of focusingon conventional therapeutics that target in vitro bacterial viability, an alternative therapy is to target virulence factors andbiofilms. Such anti-virulence strategies have attracted more and more attention rencently, for it would add both supplementand diversity to our current antimicrobial library. This approach has several potential advantages including imposingless evolutionary pressure on the development of antibiotic resistance, increasing the antibacterial targets and preservingthe host endogenous microbiome. Quorum sensing is an intercellular communication process in bacterial communities,which can regulate coordinated expression of virulence factors and biofilms. N-Acyl homoserine lactones (AHLs) areautoinducers generated by a variety of Gram-negative bacteria. These signals combining with their cognate LuxR-type receptorstrigger the expression of virulence genes. In this critical review, we summarize various structual types of smallmolecules targeting AHL-based quorum sensing to attenuate bacteria virulence factors and biofilms.

Adenosine A2A Receptor Antagonists as Positron Emission Tomography (PET) Tracers by S. Khanapur, A. van Waarde, K. Ishiwata, K. L. Leenders, R. A.J.O. Dierckx, P. H. Elsinga (312-328).
The adenosine A2A receptor (A2AR) is highly concentrated in the striatum, and a therapeutic target for Parkinson'sdisorder (PD) and Huntington's disease. High affinity and selective radiolabeled A2AR antagonists can be importantresearch and diagnostic tools for PD. Positron Emission Tomography (PET) can play an important role by measuring radiolabeledA2A antagonists non-invasively in the brain. However, till date no complete review on A2AR PET ligands isavailable. The present article has been therefore focused on available PET tracers for A2AR and their detailed biologicalevaluation in rodents, nonhuman primates and humans. Drug design and development by molecular modeling includingnew lead structures that are potential candidates for radiolabeling and mapping of cerebral A2ARs is discussed in the presentarticle. A brief overview of functions of adenosine in health and disease, including the relevance of A2AR for PD hasalso been presented.

The long-term usage of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) eventually leads torapid emergence of drug-resistant viruses and severe side effect. Therefore, it is imperative to seek the additional NNRTIswith potent and broad spectrum anti-mutant activities, and excellent pharmacokinetic profiles. The discovery of etravirine,rilpivirine and other successful examples has influenced the NNRTIs design strategy profoundly. Sustained efforts in thisarea have led to the identification of many promising NNRTIs hits, leads and candidates for the last few years. Hence, thisreview aims to highlight recent prominent advances in this field as well as contributions from our laboratory toward thediscovery of novel potent NNRTIs from 2009 to 2013 (by May).

Alzheimers Disease and Oxidative Stress: A Review by Miroslav Pohanka (356-364).
Alzheimer's disease (AD) is a neurodegenerative disorder with no known cure and rapid rise in incidence. Thepredominant cognitive impairment is currently treated using cognitive enhancers like cholinesterase inhibitors. The twomolecular hallmarks of AD are amyloid plaques created from an amyloid precursor protein and hyperphosphorylated tauprotein that is deposited as neurofibrillary tangles inside neurons. A number of pathological mechanisms follow or precedethese formations. Alteration in mitochondrial function and deposition of heavy metals are reported. The disease progressionis enhanced by oxidative stress. However, the role of oxidative stress is not universally accepted. The current reviewcovers and discusses the basic evidence and role of oxidative stress in AD development.

The NOX1/4 Inhibitor GKT136901 as Selective and Direct Scavenger of Peroxynitrite by S. Schildknecht, A. Weber, H. R. Gerding, R. Pape, M. Robotta, M. Drescher, A. Marquardt, A. Daiber, B. Ferger, M. Leist (365-376).
NADPH oxidases (NOX), catalyzing the reduction of molecular oxygen to form the superoxide radical anion(.O2-) and hydrogen peroxide (H2O2), are involved in several pathological conditions, such as stroke, diabetes, atherosclerosis,but also in chronic neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, or multiple sclerosis.GKT136901 is a novel NOX-1/4 inhibitor with potential application in the areas of diabetic nephropathy, stroke, orneurodegeneration. In the present study, we investigated additional pharmacological activities of the compound with respectto direct free radical scavenging. GKT136901 did not interact with nitric oxide (.NO), .O2-, or hydroxyl radicals(.OH), but it acted as selective scavenger of peroxynitrite (PON) already in the submicromolar concentration range. Alphasynuclein (ASYN) is a protein involved in the pathogenesis of Parkinson's disease and a known target for PON-dependenttyrosine nitration. Submicromolar concentrations of GKT136901 prevented tyrosine nitration and di-tyrosine-dependentdimer formation of ASYN by PON as indicated by Western blot and mass spectrometric analysis. GKT136901 itself wasdegraded when exposed to PON. In a human neuronal cell model, GKT136901 prevented both the depletion of reducedintracellular glutathione, and the degeneration of neurites when present during PON treatment of the cells. WhenGKT136901 was applied after PON treatment, no protective effect was observed, thus excluding an impact ofGKT136901 on cellular death/survival pathways. In summary, selective scavenging of PON is an additional pharmacologicalproperty of the NOX-1/4 inhibitor GKT136901, and this may add to the efficiency of the drug in several diseasemodels.

Background: Photodynamic therapy (PDT) has been successfully used to treat various solid tumors. However,some cancer types respond poorly to PDT, including urothelial carcinomas, nasopharyngeal carcinomas, and extrahepaticcholangiocarcinomas. The therapeutic recalcitrance is in part due to the use of photosensitizers with suboptimal optical/photochemical properties and unfavorable pharmacokinetics. Objective: To circumvent these drawbacks, a secondgenerationphotosensitizer with improved optical/photochemical properties, zinc phthalocyanine (ZnPC), was encapsulatedin interstitially targeted, polyethylene glycol-coated liposomes (ITLs) intended for systemic administration. TheZnPC-ITLs were examined for reactive oxygen species (ROS) generation and oxidation capacity and validated for tumoricidalefficacy in human extrahepatic cholangiocarcinoma (Sk-Cha1) cells. ZnPC-ITL uptake and the mechanism andmode of PDT-induced cell death were studied. Methods: The ITL formulation was optimized on the basis of fluorescencespectroscopy and photon correlation spectroscopy. The extent of ROS generation, protein oxidation, and membrane oxidationwere determined by the 2',7'-dichlorodihydrofluorescein, tryptophan oxidation, and calcein leakage assays, respectively.PDT efficacy was evaluated by measuring mitochondrial activity and apoptosis-/necrosis-specific staining in combinationwith flow cytometry. The uptake of fluorescently labeled ITLs was assayed by confocal microscopy, flow cytometry,and fluorescence spectroscopy. Results: ZnPC-ITLs exhibited maximum ROS-generating and oxidation potentialat a ZnPC:lipid molar ratio of 0.003. PDT of Sk-Cha1 cells incubated with ZnPC-ITLs induced cell death in a lipid concentration-dependent manner. The mode of PDT-induced cell death comprised both apoptosis and necrosis, with necroticcell death predominating. Post-PDT cell death was attributable to pre-PDT ZnPC-ITL uptake by cancer cells, which wasmore efficient at smaller ITL diameters and a more positive surface charge. Conclusions: ZnPC-ITLs constitute ananoparticulate photosensitizer delivery system capable of inducing apoptosis and necrosis in cultured extrahepatic cholangiocarcinomacells by PDT-mediated oxidative processes. PDT-induced cell death is dependent on the extent of ITLuptake, which in turn relies on ITL size and zeta potential.