RT Journal Article SR Electronic T1 Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 664 OP 673 DO 10.1124/mol.119.117713 VO 96 IS 5 A1 Dmitry S. Lebedev A1 Elena V. Kryukova A1 Igor A. Ivanov A1 Natalia S. Egorova A1 Nikita D. Timofeev A1 Ekaterina N. Spirova A1 Elizaveta Yu. Tufanova A1 Andrei E. Siniavin A1 Denis S. Kudryavtsev A1 Igor E. Kasheverov A1 Marios Zouridakis A1 Ramaz Katsarava A1 Nino Zavradashvili A1 Ia Iagorshvili A1 Socrates J. Tzartos A1 Victor I. Tsetlin YR 2019 UL http://molpharm.aspetjournals.org/content/96/5/664.abstract AB Many peptide ligands of nicotinic acetylcholine receptors (nAChRs) contain a large number of positively charged amino acid residues, a striking example being conotoxins RgIA and GeXIVA from marine mollusk venom, with an arginine content of >30%. To determine whether peptides built exclusively from arginine residues will interact with different nAChR subtypes or with their structural homologs such as the acetylcholine-binding protein and ligand-binding domain of the nAChR α9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated α-bungarotoxin, two-electrode voltage-clamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, α7 nAChRs, and α3β2 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC50 = 157 nM) and for the α9α10 subtype by R8 and R16 (IC50 = 44 and 120 nM, respectively). Since the R8 affinity for other tested nAChRs was 100-fold lower, R8 appears to be a selective antagonist of α9α10 nAChR. For R8, the electrophysiological and competition experiments indicated the existence of two distinct binding sites on α9α10 nAChR. Since modified oligoarginines and other cationic molecules are widely used as cell-penetrating peptides, we studied several cationic polymers and demonstrated their nAChR inhibitory activity.SIGNIFICANT STATEMENT By using radioligand analysis, electrophysiology, and calcium imaging, we found that oligoarginine peptides are a new group of inhibitors for muscle nicotinic acetylcholine receptors (nAChRs) and some neuronal nAChRs, the most active being those with 16 and 8 Arg residues. Such compounds and other cationic polymers are cell-penetrating tools for drug delivery, and we also demonstrated the inhibition of nAChRs for several of the latter. Possible positive and negative consequences of such an action should be taken into account.