Source 1primary paper2017Chemical Science
Toolkit/TOP271
TOP271
Taxonomy: Mechanism Branch / Component. Workflows sit above the mechanism and technique branches rather than replacing them.
Summary
The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro.
Usefulness & Problems
No literature-backed usefulness or problem-fit explainer has been materialized for this record yet.
Published Workflows
Objective: Design and identify a photoswitchable ANP-derived peptidomimetic that enables optical control of NPR-A-linked cGMP signaling and downstream physiology.
Why it works: The workflow is based on incorporating a photochromic amino acid into an ANP-derived peptide backbone so that light-dependent isomerization changes ligand activity at NPR-A and thereby modulates cGMP signaling.
cis/trans photoisomer-dependent modulation of NPR-A signalingoptically induced conformational control of receptor activationdesign and synthesis of a small library of photoswitchable peptidomimeticsphotopharmacological testing
Stages
- 1.Design and synthesis of a small library of photoswitchable ANP-derived peptidomimetics(library_build)
This stage creates candidate ligands capable of light-dependent conformational switching while preserving the ANP-derived hormone framework.
Selection: Generate ANP-based peptidomimetics containing the photochromic amino acid AMPP in the peptide backbone.
- 2.In vitro identification of a lead photoswitchable peptidomimetic(broad_screen)
This stage identifies a ligand with measurable photoswitch-dependent signaling differences before moving to more complex ex vivo systems.
Selection: Differential NPR-A-mediated cGMP synthesis between cis and trans isomers.
- 3.Ex vivo functional validation of optical control(confirmatory_validation)
This stage tests whether the lead ligand's in vitro photoswitching translates into ex vivo control of tissue-level physiology.
Selection: Demonstrate reversible light-controlled cGMP-linked physiological effects in explanted tissues.
Steps
- 1.Incorporate AMPP into the backbone of ANP-derived peptidomimeticsphotochromic amino acid building block
Create photoswitchable ANP-derived ligand candidates.
Backbone incorporation of the photochromic amino acid is the enabling design step needed before any candidate ligands can be synthesized and tested.
- 2.Measure NPR-A-mediated cGMP synthesis for cis and trans TOP271 isomers in vitrolead photoswitchable ligand candidate
Determine whether light-switchable isomer states produce differential receptor signaling.
An in vitro signaling assay provides an initial functional readout to identify a lead candidate before testing more complex ex vivo physiology.
- 3.Test whether TOP271 enables reversible light-controlled physiology ex vivovalidated photoswitchable ligand
Confirm that the lead ligand can control endogenous receptor-linked physiology in explanted tissues.
Ex vivo testing follows in vitro signaling because it is a higher-fidelity validation of whether receptor photoswitching translates into tissue function.
Taxonomy & Function
Primary hierarchy
Mechanism Branch
Component: A low-level protein part used inside a larger architecture that realizes a mechanism.
Mechanisms
conformational uncagingConformational Uncagingphotoisomerizationreversible optical switching of receptor activityTechniques
No technique tags yet.
Target processes
recombinationInput: Light
Validation
Cell-freeBacteriaMammalianMouseHumanTherapeuticIndep. Replication
Supporting Sources
Ranked Claims
TOP271 cis and trans isomers exhibit a four-fold difference in NPR-A-mediated cGMP synthesis in vitro.
The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro.
cis trans activity difference 4 fold
Application of TOP271 allows reversible generation of cGMP using light and remote control over vasoactivity in explanted murine aortic rings and pancreatic beta cell function in islets of Langerhans.
Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans.
TOP271 enables large optically induced conformational changes ex vivo and transforms NPR-A into an endogenous photoswitch.
Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch.
The study presents TOP271 as broadly applicable to enzyme-dependent signalling processes and as extending photoswitchable molecules to transmembrane receptors.
This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.
Approval Evidence
1 source4 linked approval claimsfirst-pass slug top271
The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro.
Source:
activity differencesupports
TOP271 cis and trans isomers exhibit a four-fold difference in NPR-A-mediated cGMP synthesis in vitro.
The cis- and trans-isomers of one of our peptidomimetics, termed TOP271, exhibit a four-fold difference in NPR-A mediated cGMP synthesis in vitro.
Source:
applicationsupports
Application of TOP271 allows reversible generation of cGMP using light and remote control over vasoactivity in explanted murine aortic rings and pancreatic beta cell function in islets of Langerhans.
Thus, application of TOP271 allows the reversible generation of cGMP using light and remote control can be afforded over vasoactivity in explanted murine aortic rings, as well as pancreatic beta cell function in islets of Langerhans.
Source:
mechanism or functionsupports
TOP271 enables large optically induced conformational changes ex vivo and transforms NPR-A into an endogenous photoswitch.
Despite this seemingly small difference, TOP271 enables large, optically-induced conformational changes ex vivo and transforms the NPR-A into an endogenous photoswitch.
Source:
scope statementsupports
The study presents TOP271 as broadly applicable to enzyme-dependent signalling processes and as extending photoswitchable molecules to transmembrane receptors.
This study demonstrates the broad applicability of TOP271 to enzyme-dependent signalling processes, extends the toolbox of photoswitchable molecules to all classes of transmembrane receptors and utilizes photopharmacology to deduce receptor activation on a molecular level.
Source:
Comparisons
No literature-backed comparison notes have been materialized for this record yet.
Ranked Citations
- 1.