Chemokine Receptors and HIVAssociated Dementia

HIV-associated dementia (HAD) is a cognitive and motor dysfunction observed after infection with HIV-1 (Kaul et al., 2001). Although about one-half of children and one-fourth of adults infected with HIV-1 eventually develop the dementia (Lipton and Gendelman, 1995 McArthur et al., 2003), there is no specific treatment for HAD. In recent years, chemokine receptors have been found to play important roles in the pathogenesis of HIV-1 infection, including HAD. In a plausible model, HIV-1 enters...

Chemokine Receptors and Allergic Asthma

Allergic asthma is often characterized by airway inflammation of different cell types, airway hyper-responsiveness (AHR), mucus production, and a variable airflow (Busse, 2001 O'Byrne and Parameswaran, 2001). The initiating phase is characterized by IgE and mast cells. In the propagation phase, Th2-polarized T-lymphocytes and eosinophils are guided to a chronic inflammatory state by infiltrating the airways. The effector phase is characterized by the production of spasmogenic substances, AHR,...

Conclusion And Future Prospects

With the ingenious use of various genetic manipulations such as conditional knock-ins or knockouts with an appropriate genetic strain of rodents in combination with diet- or drug-induced regimens, there is a wide range of possibilities for testing the functions of genes. Once the therapeutic potential of a target has been established by these animal models, lead candidate compounds can also be tested in these models to study their on-target and off-target effects. A compound designed to...

Rodent Models Of Human Diseases

Years of traditional breeding, crossing, and selecting desirable phenotypes from different strains have yielded a number of mouse lines that show phenotypic similarity to human diseases. Mapping and crossing of these lines reveal the genetic markers or loci that are linked to the phenotypes. For instance, the obese and insulin-resistant strains of ob ob and db db mice and fa fa mutations in Kolestsky, ZDF, and Zucker rats are shown to be defective in leptin and its receptor (Chen et al., 1996...

Phosphodiesterase1 and

Phosphodiesterase types 1 (PDE-1) and 5 (PDE-5) are the major cGMP hydrolyzing enzymes in blood vessels and regulate the level of the mediator in concert with guanylyl cyclase, which catalyzes the synthesis of cGMP from GTP. PDE-1 and -5 have also been found in platelets. Therefore, inhibitors of PDE-1 and -5 are expected as therapeutics for cardiovascular diseases, such as hypertension, angina, cardiac failure, and obstructive arteriosclerosis (Wallis et al., 1999). Yamazaki et al. (2005) used...

De Novo Ligand Design

With known 3D structure targets (enzymes or proteins), new inhibitors or ligands can be designed de novo. De novo design programs try to construct novel structures, using sets of predefined fragments, into an active site or onto a pharmacophore model. The combinatorial nature of de novo design leads to a large amount of chemical structures. GRID (Goodford, 1985) is the first de novo method. Then, de novo ligand design programs such as LEGEND (Nishibta and Itai, 1993), LeapFrog (http...

Introduction To Parp And Parg

Driven by DNA damage, the poly(ADP-ribose) polymerases (PARPs) utilize NAD+ to create poly(ADP-ribose) (PAR) on the glutamic acid residues of proteins, drastically altering the overall charge and size of the modified protein and ultimately initiating DNA repair (Biirkle, 2001). PAR biopolymers consist of up to 200 ADP-ribose units, and polymer levels may increase more than 100-fold in minutes (Meyer-Ficca et al., 2004). This poly(ADP-ribosyl)ation of proteins is transient, because the enzyme...

Human Rhinovirus Coat Protein

The human rhinovirus (HRV) belongs to the family of picornaviruses and is the main cause for common colds and a variety of other respiratory illnesses, including otitis media and sinusitis, and for exacerbations of asthma and reactive airways disease. These illnesses still lack effective antiviral treatment. The viral capsid is a promising and intensively studied target for drug development. This protein shell encapsulates a single, positive RNA strand and consists of 60 copies of four...

References

R., Kamanda, W. S., Pettit, G. R., Hamdan, M., Mohamed, A. N., Chelladurai, B., and Mohammad, R. M. (1998). Bryostatin 1 down-regulates mdrl and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin Cancer Res 4, 1305-1314. Baryza, J. L., Brenner, S. E., Craske, M. L., Meyer, T., and Wender, P. A. (2004). Simplified analogues of bryostatin with anticancer activity display greater potency for translocation of PKCdelta-GFP. Chem Biol 11,...

Nonhuman Primate Models For Metabolic Diseases And Drug Discovery

Despite the progress made in creating more humanized rodents to produce more predictive disease models, the differences in physiology and metabolism in particular have raised concern about the relevancy of data obtained from some rodent models. Noticeably, the metabolic regulatory pathways governing the biosynthesis of cholesterol and bile acids in the liver are not entirely conserved between primates and rodents. In humans, one of the major risk factors for the development of atherosclerosis...

SARSCoV Protease

Severe acute respiratory syndrome (SARS) is a respiratory illness that had a widespread dramatic outbreak in Asia, North America, and Europe in early 2003 (Lee et al., 2003). Evidence indicates that a previously unrecognized coronavirus exists, called SARS coronavirus, which is the leading hypothesis for the cause of SARS (Rota et al., 2003). It was known that the cleavage process of the SARS-CoV polyproteins by a special proteinase, the so-called SARS coronavirus 3C-like proteinase (CoV Mpro),...

Excitotoxicity

18.2.1 Definition and Clinical Relevance The ability of the nervous system to rapidly convey sensory information and complex motor commands from one part of the body to another, and to form thoughts and memories, is largely dependent on a single powerful excitatory neurotransmitter, glutamate. There are other excitatory neurotransmitters in the brain, but glutamate is the most common and widely distributed. Most neurons (and also glia) contain high concentrations of glutamate ( 10 mM) (Lipton...

Introduction

Neurologic diseases are among the leading causes of death, disability, and economic expense in the world. For example, Alzheimer's disease (AD) ranks fourth as a cause of mortality in the United States. In fact, it has been estimated that as the population continues to age, treatment of patients with dementia will consume our entire gross national product by the latter decades of this century. Excitotoxic cell death, also termed excitotoxicity, is thought to contribute to neuronal cell injury...

Conclusions And Future Prospects

Because of the complicated mechanisms of neruodegenerative disease, there are still few available clinical therapeutants for these diseases' treatment. All available drugs for the treatment of frequently occurring neurodegenerative disorders such as Alzheimer's and Parkinson's diseases only alleviate symptoms and delay the neuronal atrophy by compensating or increasing impairments of the neurotransmit-ter metabolism (Brodaty, 1999 Grunblatt et al., 2000). Growth factors such as BDNF, GDNF, NGF,...

Nonimmunosuppressant Neuroimmunophilin Ligands

As mentioned above, the best way to treat neurodegenerative disease is by using small organic molecular NGF-like compounds. Neuroimmunophilin ligands seem to be the best choice at present. However, the unwanted immunosuppressive response limits their clinical application. It invokes the research of neuroimmunophilin ligands, which satisfies the demand of neurodisorder disease treatment without immunosup-pressive activity. Design and synthesis of low-molecular-mass, monofunctional FKBP ligands...

Memantine Binding

Figure 18.4 Paradoxically, a fixed dose of memantine (i.e., 6 pM) blocks the effect of increasing concentrations of NMDA to a greater degree than lower concentrations of NMDA. This finding is characteristic of an uncompetitive antagonist. within the effective range of its NMDA-antagonistic action (K pM) but is below the effective level of memantine at any other known receptor or ligand-gated channel (Chen et al. 1992, but see below). The antagonistic action of memantine on NMDARs is therefore...

QSAR and Recursive Partitioning

Quantitative structure-activity relationship QSAR methods were some of the earliest developed to predict drug activity, where a relationship was found between drug activity and hydrophobicity as measured by log P Hansch et al., 1986 . The same methods have also been used to predict other properties, such as those associated with ADME Tox, where the term used is quantitative structure-property relationships QSPR Grover et al., 2000a, 2000b . The essence of all the methods is to derive a...

Protein Kinase

Epidermal Growth Factor Receptor EGFR EGFR is a member of the protein tyrosine kinase family and is frequently overexpressed in cancer cells, correlating with poor prognosis and survival Normanno et al., 2005 . EGFR therefore represents a rational target for the development of novel anticancer therapies. Inhibition of the EGFR tyrosine kinase activity by small molecules has proved to be effective for the treatment of cancer Shawver et al., 2002 . Cavasotto et al. 2006 used the X-ray crystal...

Application of SMMChemokines to Probe Signaling Pathways Involved in HIVAssociated Dementia

Jnk Pathway Antiviral

To understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HIV-associated dementia HAD , we have also applied SMM-chemokine analogues derived from natural SDF-1 a or vMIP-II as chemical probes of the mechanism s whereby these SMM-chemokines prevent or promote neuronal apoptosis. Because of the profound activities of chemokine receptors in HAD, developing selective, potent inhibitors of chemokine receptors and understanding the physiological or pathological...

Virtual Screening Of Chemical Libraries

The various force-field scoring functions are based on the different molecular mechanics of the force-field parameters used in the different programs. These scoring functions typically measure only the potential energy of the system by quantifying the sum of the energies between the receptor-ligand interaction energy and the internal ligand energy induced by binding. Most force-field scoring functions consider only one protein conformation, which greatly simplifies the actual scenario. The...

W Os

Figure 15.1 An interplay between cell membrane and nuclear signaling in RA AS2O3 therapy for APL. Figure 15.1 An interplay between cell membrane and nuclear signaling in RA AS2O3 therapy for APL. these two agents cooperate at the molecular level With the recent efforts made in experimental studies, the mechanisms involved in cross-talk between RA and IFNs are being gradually unveiled 1 IFNs are found to be capable of modulating the expresssion of RA receptors in APL cells and thus ultimately...

Docking

Virtual Docking

When the crystal structure of the target is available, there is an opportunity to employ docking methodologies, whereby in a computational simulation ligands are oriented P H-bond acceptor donor, - charge, hydrophobic, aromatic D 2-4.5, 4,5-7,7-10, 10-14, 14-19,19-24 A Binary fingerprints Moll 000000100110101 0 Mol2 000000100010101 1 Mol3 001000100000100 0 Figure 3.4 Pharmacophore fingerprinting a The definition of a three-point pharmacophore, consisting of three pharmacophore points separated...

In Vivo Studies

7.5.1 Studies with DNA Intercalators The second-generation intercalator-like PARG inhibitors are ideal for in vivo studies due to their low molecular weights and good cell permeability properties. One member of the Tilorone family of PARG inhibitors, GPI 16552 or 2,7-bis has exhibited neuroprotec-tive properties in a rat model of focal cerebral ischemia. Both a 30-minute pre-ischemia treatment or a 1- or 2-hour post-ischemia treatment with GPI 16552 reduces the total infarct volume by 47-53 ,...

GPCRs

Serotonin, Tachykinin NK1, Dopamine D2, and Chemokine CCR3 Receptors G-protein-coupled receptors GPCRs are implicated in many human diseases, such as inflammation, hypertension, pain, depression, obesity, depression, and anxiety. As a result, they are the targets for nearly 50 of all drug-discovery programs Klabunde and Hessler, 2002 . GPCRs are especially challenging targets because they are membrane-bound proteins, which make their experimental 3D structure determination difficult. Although...

Oh

Figure 10.4 Crixivan bound to HIV protease taken from www.biotech100.com . See color plates. Figure 10.4 Crixivan bound to HIV protease taken from www.biotech100.com . See color plates. 10.2.3 Pharmacological Implications of Chiral Drugs Molecular chirality is a fundamental consideration in drug discovery Zhang et al., 2005 . In the asymmetric environment of receptors and enzymes, two enantiomers of chiral drugs may form different spatial relationships therefore, there may be significant...

Neuroregenerative Mechanism Of Neuroimmunophilin Ligands

The neuroregenerative mechanism of neuroimmunophilin ligands is poorly known. The original mechanism is based on the calcineurin and Ca2 channel. Dawson et al. 1993 assumed that the complex of FKBP12 and FK506 inhibits the function of calcineurin and in turn inhibits the activity of nitric oxidate synthase NOS , which makes FK506 produce the neuroprotective activity in focal ischemia. However, the evidence that nonimmunosuppressive analogues of FK506 that bind FKBP12 but can't complex with...

Dipeptidyl Peptidase Iv Dppiv

DPP-IV is a membrane-bound, homodimeric class II protein with a molecular weight of 110-150 kD per subunit. It is bound to the membrane by a transmembrane sequence of approximately 22 amino acids. The six cytosolic amino acids play no role in the binding functions. In addition to its protease function, DPP-IV has receptor properties and is an extracellular binding protein Lambeir et al., 2003 . DPP-IV has been regarded as one of the most promising therapeutic targets for the treatment of type 2...

Contributors

Jing An, University of Illinois at Urbana-Champaign, Urban, IL 61801 The Burnham Institute for Medical Research, La Jolla, CA 92037 and Raylight Corporation, Chemokine Pharmaceutical Inc., La Jolla, CA 92037, USA Tiba Aynechi, Department of Pharmeceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA Jeremy L. Baryza, Department of Chemistry, Stanford University, Stanford, CA 94305, USA Natasja Brooijmans, Graduate Program in Chemistry and Chemical Biology,...