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Biomedical subjects

Jeffrey R Peterson

Publications and source records attributed to Jeffrey R Peterson.

9 recordsLinked to original sources
PubMed2006

Reactive oxygen species in the neuropathogenesis of hypertension.

New evidence that has emerged during the past several years clearly demonstrates that reactive oxygen species (ROS) in the brain play a crucial role in blood pressure regulation by serving as signaling molecules within neurons of cardiovascular control regions. In the forebrain, midbrain, and hindbrain, a key role for oxidant stress in the pathogenesis of angiotensin II-dependent and various other models of neurogenic hypertension has also been uncovered. As in the peripheral vasculature, NAD(P)H oxidase appears to be a major enzymatic source of brain ROS, and various homologues of the catalytic subunit of this enzyme appear to be differentially localized to cardiovascular-regulating nuclei in the brain. Recent studies have begun to elucidate the downstream effects of ROS in neurons, and it is now clear that ROS may interact with a number of well-described intracellular signaling pathways involved in neuronal activation. These exciting new discoveries have furthered our understanding of the pathogenesis of neurogenic hypertension and may ultimately lead to the development of new treatments. In this review, we discuss recent evidence in support of a role for brain ROS in the pathogenesis of hypertension and summarize current studies aimed at uncovering the complex mechanisms by which brain ROS regulate blood pressure in both health and cardiovascular disease.

Angiotensin II↗
PubMed2006

Biochemical suppression of small-molecule inhibitors: a strategy to identify inhibitor targets and signaling pathway components.

Identification of small-molecule targets remains an important challenge for chemical genetics. We report an approach for target identification and protein discovery based on functional suppression of chemical inhibition in vitro. We discovered pirl1, an inhibitor of actin assembly, in a screen conducted with cytoplasmic extracts. Pirl1 was used to partially inhibit actin assembly in the same assay, and concentrated biochemical fractions of cytoplasmic extracts were added to find activities that suppressed pirl1 inhibition. Two activities were detected, separately purified, and identified as Arp2/3 complex and Cdc42/RhoGDI complex, both known regulators of actin assembly. We show that pirl1 directly inhibits activation of Cdc42/RhoGDI, but that Arp2/3 complex represents a downstream suppressor. This work introduces a general method for using low-micromolar chemical inhibitors to identify both inhibitor targets and other components of a signaling pathway.

Actin-Related Protein 2-3 Complex↗
PubMed2005

Secramine inhibits Cdc42-dependent functions in cells and Cdc42 activation in vitro.

Inspired by the usefulness of small molecules to study membrane traffic, we used high-throughput synthesis and phenotypic screening to discover secramine, a molecule that inhibits membrane traffic out of the Golgi apparatus by an unknown mechanism. We report here that secramine inhibits activation of the Rho GTPase Cdc42, a protein involved in membrane traffic, by a mechanism dependent upon the guanine dissociation inhibitor RhoGDI. RhoGDI binds Cdc42 and antagonizes its membrane association, nucleotide exchange and effector binding. In vitro, secramine inhibits Cdc42 binding to membranes, GTP and effectors in a RhoGDI-dependent manner. In cells, secramine mimics the effects of dominant-negative Cdc42 expression on protein export from the Golgi and on Golgi polarization in migrating cells. RhoGDI-dependent Cdc42 inhibition by secramine illustrates a new way to inhibit Rho GTPases with small molecules and provides a new means to study Cdc42, RhoGDI and the cellular processes they mediate.

Actins↗
PubMed2005

Geometric diversity through permutation of backbone configuration in cyclic peptide libraries.

Cyclic peptides offer the possibility of varying both scaffold geometry and R-group functionality. For example, parameters such as ring size and the placement of D-amino acid and proline residues can have a dramatic effect on the conformations of cyclic peptides, allowing access to structurally diverse species based on simple modifications in their linear sequences. We synthesized a cyclic peptide library in which ring size, alpha-carbon stereochemistry, and proline placement were varied. Analysis of the products showed that heptapeptides in general cyclized more readily than hexapeptides, and within these groups the scaffolds with a greater number of pralines cyclized with markedly lower yields than scaffolds with fewer pralines. Split-pool libraries based on a sample set of these scaffolds showed that, in general, scaffold geometry outweighed side chains variation in determining cyclization efficiency. These concepts were applied to the synthesis of cyclodimeric variants of an inhibitor of actin assembly in Xenopus egg extracts, yielding side chain variants with improved potency over the original scaffold.

Actins↗
PubMed2004

Autoinhibited proteins as promising drug targets.

Current drug discovery efforts generally focus on a limited number of protein classes, typically including proteins with well-defined catalytic active sites (e.g., kinases) or ligand binding sites (e.g., G protein-coupled receptors). Nevertheless, many clinically important pathways are mediated by proteins with no such obvious targets for small molecule inhibitors. Allosteric inhibitors offer an alternative approach to inhibition of protein activities, particularly for proteins that undergo conformational changes as part of their activity cycle. Proteins regulated by autoinhibitory domains represent one broad class of proteins that meets this criterion. In this article, we discuss the potential of autoinhibited proteins as targets for allosteric inhibitors and describe two examples of small molecules that act by stabilizing native autoinhibited conformations of their targets. We propose that proteins regulated by autoinhibition may be generally amenable to allosteric inhibition by small molecules that stabilize the native, autoinhibited fold.

Allosteric Site↗
PubMed2004

Chemical inhibition of N-WASP by stabilization of a native autoinhibited conformation.

Current drug discovery efforts focus primarily on proteins with defined enzymatic or small molecule binding sites. Autoregulatory domains represent attractive alternative targets for small molecule inhibitors because they also occur in noncatalytic proteins and because allosteric inhibitors may avoid specificity problems inherent in active site-directed inhibitors. We report here the identification of wiskostatin, a chemical inhibitor of the neural Wiskott-Aldrich syndrome protein (N-WASP). Wiskostatin interacts with a cleft in the regulatory GTPase-binding domain (GBD) of WASP in the solution structure of the complex. Wiskostatin induces folding of the isolated, unstructured GBD into its autoinhibited conformation, suggesting that wiskostatin functions by stabilizing N-WASP in its autoinhibited state. The use of small molecules to bias conformational equilibria represents a potentially general strategy for chemical inhibition of autoinhibited proteins, even in cases where such sites have not been naturally evolved in a target.

Allosteric Site↗
PubMed2004

Gender differences in the left inferior frontal gyrus in normal children.

This study examined frontal lobe subregions in 46 normal children and adolescents (25 females, mean age: 11.08, SD: 3.07; and 21 males, mean age: 10.76, SD: 2.61) to assess the effects of age and gender on volumetric measures as well as hemispheric asymmetries. Superior, middle, inferior, and orbito-frontal gray, white, and cerebrospinal (CSF) volumes were manually delineated in high-resolution magnetic resonance imaging (MRI) data to assess possible morphological changes. We report a significant age-related increase in the white matter of the left inferior frontal gyrus (IFG) in boys (P = 0.007). Additionally, the left IFG was significantly larger in boys compared to girls (P = 0.004). Boys showed increased gray matter volume relative to girls even after correcting for total cerebral volume. Also, boys were found to have significant Right > Left asymmetry patterns with greater right hemispheric volumes for total cerebral volume, total cerebral white matter, MFG white matter, and SFG white matter (P < 0.001). Girls showed significant Right > Left asymmetry patterns in total cerebral and SFG white matter (P < 0.001). These findings suggest continued modification of the IFG during normal development in boys, and significant gender differences in IFG gray matter between boys and girls that may be possibly linked to gender differences in speech development and lateralization of language.

Age Factors↗
PubMed2002

Small molecules, big impact: a history of chemical inhibitors and the cytoskeleton.

Chemical inhibitors, whether natural products or synthetic, have had an enormous impact on the study of the eukaryotic cytoskeleton. Here we review the history of some of the most widely used cytoskeletal poisons and their influence on our understanding of cytoskeletal functions. We then highlight several new inhibitors and the targeted screens used to identify them and discuss why this approach has been successful.

Animals↗