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Mar. Drugs 2018, 16(4), 109;

Makaluvamine G from the Marine Sponge Zyzzia fuliginosa Inhibits Muscle nAChR by Binding at the Orthosteric and Allosteric Sites

Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, 117997 Moscow, Russia
Moscow Institute of Physics and Technology, Institutsky Per. 9, Dolgoprudny, 141700 Moscow Region, Russia
G.B. Elyakov Pacific Institute of Bioorganic Chemistry (PIBOC), Russian Academy of Sciences, Prospect 100 let Vladivostoku, 159, 690022 Vladivostok, Russia
Author to whom correspondence should be addressed.
Received: 18 February 2018 / Revised: 16 March 2018 / Accepted: 23 March 2018 / Published: 28 March 2018
(This article belongs to the Special Issue Marine Invertebrate Toxins)
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Diverse ligands of the muscle nicotinic acetylcholine receptor (nAChR) are used as muscle relaxants during surgery. Although a plethora of such molecules exists in the market, there is still a need for new drugs with rapid on/off-set, increased selectivity, and so forth. We found that pyrroloiminoquinone alkaloid Makaluvamine G (MG) inhibits several subtypes of nicotinic receptors and ionotropic γ-aminobutiric acid receptors, showing a higher affinity and moderate selectivity toward muscle nAChR. The action of MG on the latter was studied by a combination of electrophysiology, radioligand assay, fluorescent microscopy, and computer modeling. MG reveals a combination of competitive and un-competitive inhibition and caused an increase in the apparent desensitization rate of the murine muscle nAChR. Modeling ion channel kinetics provided evidence for MG binding in both orthosteric and allosteric sites. We also demonstrated that theα1 (G153S) mutant of the receptor, associated with the myasthenic syndrome, is more prone to inhibition by MG. Thus, MG appears to be a perspective hit molecule for the design of allosteric drugs targeting muscle nAChR, especially for treating slow-channel congenital myasthenic syndromes. View Full-Text
Keywords: marine natural products; nicotinic receptors; slow-channel; myasthenic marine natural products; nicotinic receptors; slow-channel; myasthenic

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Kudryavtsev, D.S.; Spirova, E.N.; Shelukhina, I.V.; Son, L.V.; Makarova, Y.V.; Utkina, N.K.; Kasheverov, I.E.; Tsetlin, V.I. Makaluvamine G from the Marine Sponge Zyzzia fuliginosa Inhibits Muscle nAChR by Binding at the Orthosteric and Allosteric Sites. Mar. Drugs 2018, 16, 109.

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