Current Medicinal Chemistry (v.17, #26)

The HIV-1 genomic RNA reverse transcription is an essential step in the virus cycle carried out by the viral-coded reverse transcriptase (RT), which has two associated functions: the RNA- and DNA-dependent DNA polymerase (RDDP and DDDP) function and the ribonuclease H (RNase H) function. The RNase H function catalyzes the selective hydrolysis of the RNA strand of the RNA:DNA heteroduplex replication intermediate. The RT associated activities are both essential for HIV-1 replication and validated targets for drug development, but only the polymerase function has been widely investigated as drug target. In fact, either nucleoside or non-nucleoside RT inhibitors currently used in therapy act on the polymerase associated activity. In this review, we describe the compounds, reported up to today, which inhibit the HIV-1 RNase H function, their chemical structures, the structure-activity relationships and the mechanism of action.

Ribonucleotide Reductase: A Mechanistic Portrait of Substrate Analogues Inhibitors by M.A.S. Perez, N.M.F.S.A. Cerqueira, P.A. Fernandes, M.J. Ramos (2854-2872).
Ribonucleotide reductase (RNR) is the key enzyme in the biosynthesis of deoxyribonucleotides. Several different strategies for inactivation of RNRs have been reported, including the use of substrate analogues as mechanism-based inhibitors. This article undergoes a critical analysis on the current status of ribonucleotide reductase inhibitory mechanisms by substrate analogues highlighting experimental and theoretical/computational approaches. We have summarized a general portrait of the inhibitory mechanisms and classified the nucleoside analogue inhibitors in three main classes. The critical analysis undertaken will contribute in finding new and more effective ways of inhibiting RNR.

Using Small Molecule GSK3β Inhibitors to Treat Inflammation by G. Klamer, E. Song, K-H. Ko, T.A. O'Brien, A. Dolnikov (2873-2881).
Glycogen Synthase Kinase 3 beta (GSK3and#946;) is a serine-threonine kinase originally identified for its role in the conversion of glucose to glycogen. Pharmacological inhibition can be achieved by drug binding to ATP or magnesium binding sites on the enzyme. Pharmaceutical companies have developed several small molecule GSK3and#946; inhibitors for diabetes research. Additionally, GSK3and#946; inhibitors are being clinically tested as therapeutics for neurological diseases, however, the mechanisms of involvement are unclear. Several studies have shown that the therapeutic effect of GSK3and#946; inhibition is associated with the inhibition of inflammation. Similarly, the mechanisms underlying the anti-inflammatory function of GSK3and#946; inhibition are not well understood. GSK3and#946; inhibition attenuates activation of the pro-inflammatory transcription factor NFand#954;B, and activates the immuno-modulatory transcription factor and#946;-catenin. GSK3and#946; inhibition has also been shown to induce secretion of the anti-inflammatory cytokine IL-10. In addition, pharmacological inhibition of GSK3and#946; suppressed alloreactive T-cell responses. The combined anti-proliferative and anti-inflammatory properties of small molecule inhibitors of GSK3and#946; make them an attractive treatment modality towards the control of inflammation.

Use of Kv1.3 Blockers for Inflammatory Skin Conditions by W. Nguyen, B.L. Howard, D.S. Neale, P.E. Thompson, P.J. White, H. Wulff, D.T. Manallack (2882-2896).
Recent results using animal models of inflammatory skin conditions have shown that blockers of the voltage-gated potassium channel, Kv1.3 hold great promise for clinical utility. Kv1.3 blockers act as immunosuppressants by modulating the various subsets of inflammatory T and B cells involved in autoimmune disorders. While peptidic inhibitors based on naturally occurring venoms demonstrate potent and selective Kv1.3 blockade, these require parenteral administration and may face potential immunogenicity problems. Small molecule blockers show considerable diversity, however selectivity over other Kv1-family channels has been difficult to achieve. More recent advances have added to the evidence that Kv1.3 channels are a suitable therapeutic target and that the development of novel and selective agents will herald new drugs for inflammatory skin disorders.

Regulators of Platelet cAMP Levels: Clinical and Therapeutic Implications by L. Noe, K. Peeters, B. Izzi, C. Van Geet, K. Freson (2897-2905).
Platelets are indispensable for primary haemostasis, but their function needs to be tightly regulated to prevent excessive platelet activity, possibly leading to atherothrombotic events. An important mediator of the platelet activity is cyclic AMP (cAMP), which inhibits platelet aggregation. Intracellular cAMP levels are regulated via the Gs and Gi alpha subunits of heterotrimeric G proteins, which couple to adenylyl cyclase to respectively stimulate or inhibit cAMP production. Binding of a ligand to its G protein-coupled seven-transmembrane receptor activates these G proteins. In this review, we discuss a Gs-coupled receptor on platelets, VPAC1, and 2 important Gi-coupled receptors, the ADP receptor P2Y12 and the prostaglandin E2 receptor EP3. The regulation of platelet cAMP levels at the level of the receptors themselves or the G proteins coupled to them is analyzed. Alterations in Gsand#945; and Giand#945; function are associated with altered platelet reactivity. An increase in Gs function, or alternatively a defective Gi signaling, can be a risk factor for bleeding, while a loss of Gs function can result in a prothrombotic state. Regulator of G protein signaling (RGS) proteins accelerate the rate of inactivation of G protein-mediated signaling. One of the RGS proteins, RGS2, inhibits Gs signaling by interacting directly with adenylyl cyclase. The thienopyridine class of antiplatelet agents is based on cAMP-mediated regulation of platelet function through modification of the P2Y12 receptor. Clopidogrel and some other novel cAMP regulators are discussed. Secondly, we review the use of prostacyclin derivatives to treat pulmonary arterial hypertension.

Drug Target Identification for Neuronal Apoptosis Through a Genome Scale Screening by E.A. Tendi, R. Cunsolo, D. Bellia, R.L. Messina, S. Paratore, P. Calissano, S. Cavallaro (2906-2920).
During normal nervous system development, physiologically appropriate neuronal apoptosis contributes to a sculpting process that removes approximately one-half of all neurons born during neurogenesis. However, neuronal apoptosis subsequent to this developmental window is physiologically inappropriate for most systems and can contribute to neurodegenerative diseases. Neuronal apoptosis is characterized by specific morphological events and requires the activation of an intrinsic transcriptional program. With the completion of genome sequencing in humans and model organisms, and the advent of DNA microarray technology, the transcriptional cascades and networks regulating neuronal apoptosis are being elucidated providing new potential pharmacological targets. This review will introduce the reader to this genomic approach and illustrate with a few examples a methodological strategy for the rational selection of pharmacological targets and the development of neuroprotective agents.

Sirtuin Family: A Link to Metabolic Signaling and Senescence by S. Kyrylenko, A. Baniahmad (2921-2932).
A vast collection of data obtained during the last decade supports the view on sirtuins as sensors of actual cellular metabolic state being involved in cell cycle progression, apoptosis/survival decision making, longevity, inflammation etc. Moreover, sirtuins themselves can control metabolism through their ability to consume NAD+. In turn, cellular NAD parameters may affect the generation of ATP, a main cellular currency of energy. Therefore, sirtuins became recognized as critical affectors of cellular metabolism which participate in fat mobilization, gluconeogenesis, caloric restriction etc. Cellular senescence is viewed as a mechanism to restrict excessive cell growth when it is unnecessary or harmful. It is therefore necessary to understand the mechanism of senescence to design new approaches to combat cancer. Growth in turn depends on metabolism as it requires energy. Therefore, in this review, we address the connection of sirtuins to senescence through their participation in the regulation of metabolic and biochemical parameters and related signaling.

What is Known About the Antiviral Agents Active Against Bovine Viral Diarrhea Virus (BVDV)? by L.M. Finkielsztein, G.Y. Moltrasio, M.E. Caputto, E.F. Castro, L.V. Cavallaro, A.G. Moglioni (2933-2955).
Viruses belonging to the Flaviviridae family cause clinically significant diseases in humans and animals. This family includes three genera: Pestivirus [including bovine viral diarrhea virus (BVDV)], Flavivirus [including yellow fever virus (YFV), dengue virus, and West Nile virus (WNV)], and Hepacivirus [including hepatitis C virus (HCV)]. BVDV is responsible for major losses in cattle, causing a range of clinical manifestations, and is also a problematic contaminant in the laboratory. Noncytopathic BVDV infection can remain unnoticed and infect laboratory cell lines through its presence in contaminated bovine serum used in cell culture. BVDV is considered to be a valuable surrogate virus model for identifying and characterizing antiviral agents to be used against HCV. In some aspects of viral replication, BVDV is more advantageous than the currently used HCV replicon systems. In this review, we report the design, synthesis, and activity against BVDV of a series of compounds assayed until now.

Infrared-Spectroscopy: A Non-Invasive Tool for Medical Diagnostics and Drug Analysis by H. Hahn, J.D. Pallua, C. Pezzei, V. Huck-Pezzei, G.K. Bonn, C.W. Huck (2956-2966).
Constant development enabled Infrared (IR) spectroscopy to become a widely used, non-invasive tool for fast sample analyses with less to no pre-preparation. Furthermore, computational data handling is no more a limiting factor and hence, IR measurements are predestined for clinical diagnostics and drug analysis. Within this review the focus was put on clinical topics of high interest. One example is Alzheimer's disease, where the exact metabolism is still not clarified, or blood glucose monitoring for high throughput screening of patients without taking any drop of blood. The second section of this manuscript was focused on the analysis of drugs. The detection of physico-chemical parameters in pharmaceutics and the improvement of industrial proceedings allowed a dramatic increase of quality of produced medicine. In pharmaceutical industries problems with the equable allocation of agents occurs especially in scaling up processes. IR-analyzing- techniques serve as fast and precise indicators for the detection of active components and their distribution in tablets. In combination with statistical factors and medical investigations pharmaceuticals can be improved from their development until their application, and every step can be easily controlled by IR spectroscopy.

Use of the Adamantane Structure in Medicinal Chemistry by Guy Lamoureux, Graciela Artavia (2967-2978).
This review summarizes the importance and recent discoveries of the use of adamantane derivatives in Medicinal Chemistry. We have organized the article in 4 sections: 1) Absorption, Distribution, Metabolism, or Excretion (ADME) properties 2) Hydrophobic Effects 3) Ion Channels and 4) Rigid scaffold. Within each section, we have provided examples of how the adamantane group changes the properties of known drugs or provides a important pharmacophore for the design of new drugs.

Polymeric materials play a key role in the production of medical and clinical devices thanks to their special features such as flexibility, easy processing and good price/performance ratio. Among the different polymeric matrixes, one of the most used is Poly(vinyl chloride) (PVC). At room temperature PVC is hard and brittle, thus great amounts (40- 50and#x25;) of phthalate esters that act as plasticizers are added to the polymer to make it flexible and appropriate for medical use. Di-(2-ethylhexyl)-phthalate (DEHP) is the most widely used plasticizer in PVC medical devices. However, DEHP is not chemically bound to PVC and migrates from medical devices with time and use. The potential for DEHP to produce adverse effects in humans has been the subject of considerable discussion and debate in the scientific community. In particular, newborns in the new environment have to be considered at particularly increased risk, because of their small body size and the multiple medical device-related to the DEHP exposure. The major factors determining the degree to which DEHP migrates from medical devices are temperature, amount of DEHP in the device, storage time, shaking of the device while in contact with the medical solutions and degree of PVC degradation. The Aim of this review is to present an updated outline of recent ongoing research in the field of PVC degradation and consequent release of phthalates by highlighting their impact on human health, focusing on neonatal exposure.