Carr R.,Thomas Jefferson University |
Du Y.,Stanford University |
Quoyer J.,University of Montreal |
Panettieri R.A.,University of Pennsylvania |
And 5 more authors.
Journal of Biological Chemistry | Year: 2014
The β2-adrenergic receptor (β2AR) is a prototypical G pro-tein- coupled receptor that mediates many hormonal responses, including cardiovascular and pulmonary function. β-Agonists used to combat hypercontractility in airway smooth muscle stimulate β2AR-dependent cAMP production that ultimately promotes airway relaxation. Chronic stimulation of the β2AR by long acting β-agonists used in the treatment of asthma can promote attenuated responsiveness to agonists and an increased frequency of fatal asthmatic attacks. β2AR desensitization to β-agonists is primarily mediated by G protein-coupled receptor kinases and β-arrestins that attenuate receptor-Gs coupling and promote β2AR internalization and degradation. A biased agonist that can selectively stimulate Gs signaling without promoting receptor interaction with G protein-coupled receptor kinases and β-arrestins should serve as an advantageous asthma therapeutic. To identify such molecules, we screened ∼50 lipidated peptides derived from the intracellular loops of the β2AR, known as pepducins. This screen revealed two classes of Gs- biased pepducins, receptor-independent and receptor-dependent, as well as several β-arrestin-biased pepducins. The recep-tor- independent Gs-biased pepducins operate by directly stimulating G protein activation. In contrast, receptor-dependentG s-biased pepducins appear to stabilize aGs-biased conformation of the β2AR that couples to Gs but does not undergo G protein-coupled receptor kinase-mediated phosphorylation or β-arrestin-mediated internalization. Functional studies in primary human airway smooth muscle cells demonstrate that Gs- biased pepducins are not subject to conventional desensitization and thus may be good candidates for the development of next generation asthma therapeutics. Our study reports the first Gs-biased activator of the β2AR and provides valuable tools for the study of β2AR function. © 2014 by The American Society for Biochemistry and Molecular Biology Inc. Source
DeSimone C.V.,State University of New York at Buffalo |
DeSimone C.V.,Mayo Medical School |
Zarayskiy V.V.,State University of New York at Buffalo |
Zarayskiy V.V.,Anchor Therapeutics |
And 3 more authors.
Molecular Pharmacology | Year: 2011
Kv4 (Shal) potassium channels are responsible for the transient outward K+ currents in mammalian hearts and central nervous systems. Heteropoda toxin 2 (HpTx2) is an inhibitor cysteine knot peptide toxin specific for Kv4 channels that inhibits gating of Kv4.3 in the voltage-dependent manner typical for this type of toxin. HpTx2 interacts with four independent binding sites containing two conserved hydrophobic amino acids in the S3b transmembrane segments of Kv4.3 and the closely related Kv4.1. Despite these similarities, HpTx2 interaction with Kv4.1 is considerably less voltage-dependent, has smaller shifts in the voltage-dependences of conductance and steady-state in-activation, and a 3-fold higher Kd value. Swapping four non-conserved amino acids in S3b between the two channels exchanges the phenotypic response to HpTx2. To understand these differences in gating modification, we constructed Markov models of Kv4.3 and Kv4.1 activation gating in the presence of HpTx2. Both models feature a series of voltage-dependent steps leading to a final voltage-independent transition to the open state and closely replicate the experimental data. Interaction with HpTx2 increases the energy barrier for channel opening by slowing activation and accelerating deactivation. The greater degree of voltage-dependence in Kv4.3 occurs because it is the voltage-dependent transitions that are most affected by HpTx2; in contrast, it is the voltage-independent step in Kv4.1 that is most affected by the presence of toxin. These data demonstrate the basis for subtype-specificity of HpTx2 and point the way to a general model of gating modifier toxin interaction with voltage-gated ion channels. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics. Source
Anchor Therapeutics and Ascent Therapeutics | Date: 2011-06-14
Biomedical compounds, namely, peptide screening agents for clinical or medical laboratory use in detecting or developing pharmaceutical preparations for treatment or prevention of diseases.
Anchor Therapeutics | Date: 2013-01-09
The invention relates generally to compounds which are allosteric modulators (e.g., negative and positive allosteric modulators, allosteric agonists, and ago-allosteric modulators) of the G protein coupled receptor apelin, also known as the APJ receptor. The APJ receptor compounds are derived from the it intracellular loop and domain of the APJ receptor. The invention also relates to the use of these APJ receptor compounds and pharmaceutical compositions comprising the APJ receptor compounds in the treatment of diseases and conditions associated with APJ receptor modulation, such as cardiovascular diseases, (e.g., hypertension and heart failure, such as congestive heart failure), cancer, diabetes, stem cell trafficking, fluid homeostasis, cell proliferation, immune function, obesity, metastatic disease, and HIV infection.
News Article | August 20, 2010
Anchor Therapeutics is developing first-in-class pepducin drug candidates, novel molecules that can selectively target G protein coupled receptors (GPCRs) to allosterically modulate GPCR signaling.