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The structure of anti-tumor and anti-HIV-1 plant protein MAP30, a ribosome-inactivating protein, has been investigated and structural insights into multiple functions gained. MAP30 comes from Momordica charantia, bitter melon, the extracts of which have long been used as therapeutic agents. The protein is among the largest single-chain proteins the solution structures of which have been found without a prior X-ray crystal structure. It behaves as would a DNA glycosylase/apurinic lyase.

Pregabalin is a specific ligand of the alpha2-delta (α2-δ) auxiliary subunit of voltage-gated calcium channels. A growing body of evidence from studies of anxiety and pain indicate that the observed responses with pregabalin may result from activity at the α2-δ auxiliary protein expressed presynaptically, in several different circuits of the central nervous system (CNS). The disorders that appear to be effectively treated with pregabalin are thematically linked by neuronal dysregulation or hyperexcitation within the CNS. This review proposes how binding to the α2-δ protein target in different regions of the CNS may contribute to the observed clinical activity of pregabalin, as well as to the adverse event profile of the compound. Whether this compound regulates synaptic function via α2-δ in additional conditions is yet to be discovered. The potential of pregabalin to regulate neuronal hyperactivity involving other CNS circuits will require further exploration. [Copyright &y& Elsevier]

In addition to positive, negative, aggressive and cognitive symptoms, patients with schizophrenia often exhibit affective disorders, including depression and anxiety. Affective symptoms in schizophrenia can be particularly disturbing for patients with schizophrenia, increasing the risk of suicide and diminishing quality of life. The following review examines the prevalence, etiology and treatment of affective symptoms, particularly depression, in patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Summary: Attempts to develop selective (“magic bullet”) drugs for the treatment of schizophrenia have been frustrated by the complex etiology of the disease. The symptomatology of schizophrenia does not appear to arise from a single neurobiological entity, but rather may be derived from pathology at one or more receptor types. This has prompted multifactorial approaches to the development of new therapeutics, as embodied by polypharmacy and an alternative (or augmentative) strategy known as “intramolecular polypharmacy,” in which a single drug possesses the capacity to affect multiple receptor types. Atypical antipsychotics are a well-known example of this approach; each atypical possesses a unique portfolio of activities at receptors that may contribute to therapeutic effects (as well as side effects). In this article we present a discussion of some of the receptor targets that are currently thought to mediate symptoms of schizophrenia, as well as their possible implications for the design of future multifunctional antipsychotics. [Copyright &y& Elsevier]

Abstract: Schizophrenia is a highly complex disorder characterized by multiple independent domains of disease—namely positive, cognitive, and affective symptom clusters. Functional deficits associated with positive and (more recently) cognitive symptoms, as well as the deconstruction of these symptoms into their corresponding neural circuits, are widely discussed in the literature. To the contrary, while a link between affective symptoms and emotion processing circuitry has been hypothesized, it has been considerably less widely discussed in the literature. Here, we review deficits in the processing of emotion in schizophrenia, the role of the amygdala in the context of these deficits, and the functional implications of this relationship upon patient outcome. [Copyright &y& Elsevier]

: BackgroundSerotonergic and adrenergic enhancement may be synergistic and more effective than serotonergic enhancement alone in treating depression. The dual serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine is a dual reuptake inhibitor that may therefore offer greater efficacy than selective serotonin reuptake inhibitors (SSRIs).: MethodsData from eight randomized, double-blind, controlled studies were pooled to compare efficacy in depressed patients receiving venlafaxine/venlafaxine extended release (XR), SSRIs, or placebo for ≤8 weeks. The mean changes from baseline in the 21-item Hamilton Rating Scale for Depression (HAM-D21), Montgomery–A˚sberg Depression Rating Scale (MADRS), and Clinical Global Impressions—Global Improvement (CGI-I) and CGI—Severity of Illness (CGI-S) item scores were compared, as were response rates derived from these scales.: ResultsStatistically significant differences in mean HAM-D21 score decrease between venlafaxine (14.5) and SSRIs (12.6) and between the active treatments and placebo (11.3) were observed. Venlafaxine significantly decreased the mean MADRS scores more than SSRIs (17.8 vs. 15.9), and both treatments were significantly better than placebo (12.9). The same pattern of significance for CGI-I, HAM-D21, and MADRS response rates between venlafaxine (71%, 64%, and 67%, respectively), SSRIs (64%, 57%, and 59%, respectively), and placebo (50%, 42%, and 41%, respectively) was observed.: ConclusionsVenlafaxine was significantly more effective than SSRIs in improving depression, perhaps due to enhancing both serotonin and norepinephrine. [Copyright &y& Elsevier]

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began in the 1990s when xanomeline, an M 1 /M 4 -preferring mAChR agonist developed for cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation of peripheral mAChRs were not available at that time. The discovery of specific targeted ligands and combination treatments to reduce peripheral mAChR engagement have advanced the potential of mAChR activators as effective treatments for psychotic disorders. This review provides perspectives on the background of the identification of mAChRs as potential antipsychotics, advances in the preclinical understanding of mAChRs as targets, and the current state of mAChR activators under active clinical development for schizophrenia. Effective control of psychotic (positive) symptoms is key to successful drug development targets for schizophrenia. Central mAChR agonists have shown antipsychotic activity without any direct dopamine receptor antagonism. Early attempts at developing mAChR agonists targeting psychosis were thwarted by tolerability problems from unwanted peripheral mAChR receptor activation, but recent advances aim to reduce tolerability burden. M1 and M4 receptors are the subtypes most closely linked to antipsychotic activity targets and current mAChR agonists targeting psychosis include those with central M1, M4, or dual M1/M4 receptor agonist properties. Strategies to minimize peripheral muscarinic adverse events include (i) using orthosteric, allosteric, or bitopic functionality strategies, and (ii) using a cotreatment with a peripheral muscarinic antagonist. [ABSTRACT FROM AUTHOR]

Summary Human immunodeficiency viral (HIV-1) fusion is mediated by the viral envelope gp120/gp41 complex (ENVelope glycoprotein). After gp120 shedding, gp41 is exposed and elicits membrane fusion via a cascade of conformational changes. In contrast to prefusion and postfusion conformation, little is known about any intermediate conformation. We report on a solution NMR investigation of homotrimeric HIV-1 gp41 27–194 , comprising the transmembrane region and reconstituted in dodecyl phosphocholine (DPC) micelles. The protein is mainly α-helical, but experiences internal dynamics on the nanosecond and micro to millisecond time scale and transient α-helical behavior for certain residues in the N-terminal heptad repeat (NHR). Strong lipid interactions are observed, in particular for C-terminal residues of the NHR and imunodominant loop region connecting NHR and C-terminal heptad repeat (CHR). Our data indicate an extended conformation with features anticipated for a prefusion intermediate, presumably in exchange with a lowly populated postfusion six-helical bundle conformation. [ABSTRACT FROM AUTHOR]

Summary: Chronic hepatitis B virus (HBV) infection afflicts millions worldwide with cirrhosis and liver cancer. HBV e-antigen (HBeAg), a clinical marker for disease severity, is a nonparticulate variant of the protein (core antigen, HBcAg) that forms the building-blocks of capsids. HBeAg is not required for virion production, but is implicated in establishing immune tolerance and chronic infection. Here, we report the crystal structure of HBeAg, which clarifies how the short N-terminal propeptide of HBeAg induces a radically altered mode of dimerization relative to HBcAg (∼140° rotation), locked into place through formation of intramolecular disulfide bridges. This structural switch precludes capsid assembly and engenders a distinct antigenic repertoire, explaining why the two antigens are cross-reactive at the T cell level (through sequence identity) but not at the B cell level (through conformation). The structure offers insight into how HBeAg may establish immune tolerance for HBcAg while evading its robust immunogenicity. [Copyright &y& Elsevier]

Summary: Hepatocyte growth factor (HGF) and vascular endothelial cell growth factor (VEGF) regulate normal development and homeostasis and drive disease progression in many forms of cancer. Both proteins signal by binding to receptor tyrosine kinases and heparan sulfate (HS) proteoglycans on target cell surfaces. Basic residues comprising the primary HS binding sites on HGF and VEGF provide similar surface charge distributions without underlying structural similarity. Combining three acidic amino acid substitutions in these sites in the HGF isoform NK1 or the VEGF isoform VEGF165 transformed each into potent, selective competitive antagonists of their respective normal and oncogenic signaling pathways. Our findings illustrate the importance of HS in growth factor driven cancer progression and reveal an efficient strategy for therapeutic antagonist development. [ABSTRACT FROM AUTHOR]

Mediator is a multisubunit coactivator required for initiation by RNA polymerase II. The Mediator tail subdomain, containing Med15/Gal11, is a target of the activator Gcn4 in vivo, critical for recruitment of native Mediator or the Mediator tail subdomain present in sin4Δ cells. Although several Gal11 segments were previously shown to bind Gcn4 in vitro, the importance of these interactions for recruitment of Mediator and transcriptional activation by Gcn4 in cells was unknown. We show that interaction of Gcn4 with the Mediator tail in vitro and recruitment of this subcomplex and intact Mediator to the ARG1 promoter in vivo involve additive contributions from three different segments in the N terminus of Gal11. These include the KIX domain, which is a critical target of other activators, and a region that shares a conserved motif (B-box) with mammalian coactivator SRC-1, and we establish that B-box is a critical determinant of Mediator recruitment by Gcn4. We further demonstrate that Gcn4 binds to the Gal11 KIX domain directly and, by NMR chemical shift analysis combined with mutational studies, we identify the likely binding site for Gcn4 on the KIX surface. Gcn4 is distinctive in relying on comparable contributions from multiple segments of Gal11 for efficient recruitment of Mediator in vivo. [ABSTRACT FROM AUTHOR]

Most smokers repeatedly fail in their attempts to stop smoking because of the addictive nature of the nicotine in tobacco products. Nicotine dependence is probably mediated through the activation of multiple subtypes of neuronal nicotinic acetylcholine receptor (nAChR), among which the mesolimbic α4β2 subtype has a pivotal role. Here, we discuss the rationale for and the design of α4β2 nAChR partial agonists as novel treatments for tobacco addiction. Such agents are expected to exhibit a dual action by sufficiently stimulating α4β2-nAChR-mediated dopamine release to reduce craving when quitting and by inhibiting nicotine reinforcement when smoking. Potent and selective α4β2 nAChR partial agonists that exhibit dual agonist and antagonist activity in preclinical models can be identified. The validity of this approach is demonstrated by the clinical efficacy of the α4β2 nAChR partial agonist varenicline, which has significantly better quit rates than do other treatments and offers a new option for smoking cessation pharmacotherapy. [Copyright &y& Elsevier]