Delving into the Latest Updates on ACV-1 with Synapse

Overview

Basic Info

Drug Type

Recombinant polypeptide

Synonyms

alpha-Conotoxin VC 1.1, alpha-Conotoxin VC1.1

+ [4]

Target

CHRNB4 x nAChRα9&α10

Mechanism

CHRNB4 inhibitors(Beta-4 nicotinic acetylcholine receptor inhibitors), α9α10 receptor antagonists(Neuronal acetylcholine receptor; alpha9/alpha10 antagonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

NeuralgiaNeuralgia, Postherpetic

Originator Organization

University of Melbourne

Active Organization-

Inactive Organization

Polynovo Ltd.

University of MelbourneMetabolic Pharmaceuticals Pty Ltd.

Drug Highest PhaseDiscontinuedPhase 2

First Approval Date-

Regulation-

Login to view timeline

α-Conotoxins (α-CTxs) can selectively target nicotinic acetylcholine receptors (nAChRs) and are important drug leads for the treatment of cancer, chronic pain, and neuralgia. Here, we chemically synthesized a formerly defined rat α7 nAChR targeting α-CTx Mr1.1 and evaluated its activity at human nAChRs. Mr1.1 was most potent at the human (h) α9α10 nAChR with a half-maximal inhibitory concentration (IC₅₀) of 92.0 nM. Molecular dynamic simulations suggested that Mr1.1 favorably binds at the α10(+)α9(-) and α9(+)α9(-) sites via hydrogen bonds and salt bridges, stabilizing the channel in a closed conformation. Although Mr1.1 and another antagonist, α-CTx Vc1.1 share high sequence similarity and disulfide-bond framework, Mr1.1 has distinct orientations at hα9α10. Based on the Mr1.1-hα9α10 model, analogues were generated, and the more potent Mr1.1[S4Dap], antagonized hα9α10 with an IC₅₀ of 4.0 nM. Furthermore, Mr1.1[S4Dap] displayed analgesic activity in the rat chronic constriction injury (CCI) pain model and therefore presents a promising drug candidate.

01 Oct 2022·Molecular Pharmacology

Analgesic α-Conotoxin Binding Site on the Human GABA_B Receptor

Article

Author: Wong, Ann R ; Komori, Akari ; Adams, David J ; McArthur, Jeffrey R ; Bony, Anuja R ; Hung, Andrew

The analgesic α-conotoxins Vc1.1, RgIA, and PeIA attenuate nociceptive transmission via activation of G protein-coupled GABA_B receptors (GABA_BRs) to modulate N-type calcium channels in primary afferent neurons and recombinantly coexpressed human GABA_BR and Cav2.2 channels in human embryonic kidney 293T cells. Here, we investigate the effects of analgesic α-conotoxins following the mutation of amino acid residues in the Venus flytrap (VFT) domains of the GABA_BR subunits predicted through computational peptide docking and molecular dynamics simulations. Our docking calculations predicted that all three of the α-conotoxins form close contacts with VFT residues in both B1 and B2 subunits, comprising a novel GABA_BR ligand-binding site. The effects of baclofen and α-conotoxins on the peak Ba²⁺ current (I_Ba) amplitude were investigated on wild-type and 15 GABA_BR mutants individually coexpressed with human Cav2.2 channels. Mutations at the interface of the VFT domains of both GABA_BR subunits attenuated baclofen-sensitive I_Ba inhibition by the analgesic α-conotoxins. In contrast, mutations located outside the putative peptide-binding site (D380A and R98A) did not. The key GABA_BR residues involved in interactions with the α-conotoxins are K168 and R207 on the B2 subunit and S130, S153, R162, E200, F227, and E253 on the B1 subunit. The double mutant, S130A + S153A, abolished inhibition by both baclofen and the α-conotoxins. Depolarization-activated I_Ba mediated by both wild-type and all GABA_BR mutants were inhibited by the selective GABA_BR antagonist CGP 55845. This study identifies specific residues of GABA_BR involved in the binding of the analgesic α-conotoxins to the VFT domains of the GABA_BR. SIGNIFICANCE STATEMENT: This study defines the binding site of the analgesic α-conotoxins Vc1.1, RgIA, and PeIA on the human GABA_B receptor to activate Gi/o proteins and inhibit Cav2.2 channels. Computational docking and molecular dynamics simulations of GABA_BR identified amino acids of the Venus flytrap (VFT) domains with which the α-conotoxins interact. GABA_BR alanine mutants attenuated baclofen-sensitive Cav2.2 inhibition by the α-conotoxins. We identify an allosteric binding site at the interface of the VFT domains of the GABA_BR subunits for the analgesic α-conotoxins.

01 Jan 2022·British Journal of Pharmacology

Analgesic α‐conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABA_B receptors and reduce neuroexcitability

Article

Author: Adams, David J. ; McArthur, Jeffrey R. ; Bony, Anuja R. ; Finol‐Urdaneta, Rocio K.

Background and PurposeActivation of GIRK channels via G protein‐coupled GABAB receptors has been shown to attenuate nociceptive transmission. The analgesic α‐conotoxin Vc1.1 activates GABAB receptors resulting in inhibition of Cav2.2 and Cav2.3 channels in mammalian primary afferent neurons. Here, we investigated the effects of analgesic α‐conotoxins on recombinant and native GIRK‐mediated K+ currents and on neuronal excitability.Experimental ApproachThe effects of analgesic α‐conotoxins, Vc1.1, RgIA, and PeIA, were investigated on inwardly‐rectifying K+ currents in HEK293T cells recombinantly co‐expressing either heteromeric human GIRK1/2 or homomeric GIRK2 subunits, with GABAB receptors. The effects of α‐conotoxin Vc1.1 and baclofen were studied on GIRK‐mediated K+ currents and the passive and active electrical properties of adult mouse dorsal root ganglion neurons.Key ResultsAnalgesic α‐conotoxins Vc1.1, RgIA, and PeIA potentiate inwardly‐rectifying K+ currents in HEK293T cells recombinantly expressing human GIRK1/2 channels and GABAB receptors. GABAB receptor‐dependent GIRK channel potentiation by Vc1.1 and baclofen occurs via a pertussis toxin‐sensitive G protein and is inhibited by the selective GABAB receptor antagonist CGP 55845. In adult mouse dorsal root ganglion neurons, GABAB receptor‐dependent GIRK channel potentiation by Vc1.1 and baclofen hyperpolarizes the cell membrane potential and reduces excitability.Conclusions and ImplicationsThis is the first report of GIRK channel potentiation via allosteric α‐conotoxin Vc1.1‐GABAB receptor agonism, leading to decreased neuronal excitability. Such action potentially contributes to the analgesic effects of Vc1.1 and baclofen observed in vivo.

100 Deals associated with ACV-1

Login to view more data

External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05724

R&D Status

10 top R&D records.

Login

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Neuralgia	Phase 2	-	Polynovo Ltd.	-
Neuralgia	Phase 2	AU	Metabolic Pharmaceuticals Pty Ltd.	-
Neuralgia, Postherpetic	Phase 2	-	University of Melbourne	-
Neuralgia, Postherpetic	Phase 2	AU	Polynovo Ltd.	-