Using Constellation Pharmacology to Characterize a Novel α-Conotoxin from Conus ateralbus .

Autor: Neves JLB; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR-LA), University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal.; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Urcino C; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Chase K; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Dowell C; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Hone AJ; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.; Mental Illness Research Education and Clinical Center, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA., Morgenstern D; Departments of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA., Chua VM; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Ramiro IBL; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.; The Marine Science Institute, University of the Philippines, Quezon City 1101, Philippines., Imperial JS; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Leavitt LS; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Phan J; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Fisher FA; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Watkins M; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Raghuraman S; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Tun JO; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Ueberheide BM; Departments of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016, USA., McIntosh JM; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.; Department of Psychiatry, University of Utah, Salt Lake City, UT 84108, USA.; Mental Health Department, George E. Whalen Veterans Affairs Medical Center, Salt Lake City, UT 84148, USA., Vasconcelos V; Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR-LA), University of Porto, Terminal de Cruzeiros do Porto de Leixões, Avenida General Norton de Matos, S/N, 4450-208 Matosinhos, Portugal.; Faculty of Sciences, University of Porto, Rua do Campo Alegre, 4169-007 Porto, Portugal., Olivera BM; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA., Gajewiak J; School of Biological Sciences, University of Utah, Salt Lake City, UT 84112, USA.
Jazyk: angličtina
Zdroj: Marine drugs [Mar Drugs] 2024 Feb 29; Vol. 22 (3). Date of Electronic Publication: 2024 Feb 29.
DOI: 10.3390/md22030118
Abstrakt: The venom of cone snails has been proven to be a rich source of bioactive peptides that target a variety of ion channels and receptors. α-Conotoxins (αCtx) interact with nicotinic acetylcholine receptors (nAChRs) and are powerful tools for investigating the structure and function of the various nAChR subtypes. By studying how conotoxins interact with nAChRs, we can improve our understanding of these receptors, leading to new insights into neurological diseases associated with nAChRs. Here, we describe the discovery and characterization of a novel conotoxin from Conus ateralbus , αCtx-AtIA, which has an amino acid sequence homologous to the well-described αCtx-PeIA, but with a different selectivity profile towards nAChRs. We tested the synthetic αCtx-AtIA using the calcium imaging-based Constellation Pharmacology assay on mouse DRG neurons and found that αCtx-AtIA significantly inhibited ACh-induced calcium influx in the presence of an α7 positive allosteric modulator, PNU-120596 (PNU). However, αCtx-AtIA did not display any activity in the absence of PNU. These findings were further validated using two-electrode voltage clamp electrophysiology performed on oocytes overexpressing mouse α3β4, α6/α3β4 and α7 nAChRs subtypes. We observed that αCtx-AtIA displayed no or low potency in blocking α3β4 and α6/α3β4 receptors, respectively, but improved potency and selectivity to block α7 nAChRs when compared with αCtx-PeIA. Through the synthesis of two additional analogs of αCtx-AtIA and subsequent characterization using Constellation Pharmacology, we were able to identify residue Trp18 as a major contributor to the activity of the peptide.
Databáze: MEDLINE