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

Kudryavtsev, Denis S.; Spirova, Ekaterina N.; Shelukhina, Irina V.; Son, Lina V.; Makarova, Yana V.; Utkina, N. K.; Kasheverov, Igor E.; Tsetlin, Victor I.

doi:10.3390/md16040109

Cited by 8 publications

(7 citation statements)

References 37 publications

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“…Point mutations to mouse muscle nAChR were introduced as described previously [ 6 ]. Calcium fluorescence has been measured using the Case 12 genetically encoded sensor as described by Shelukhina [ 7 ] in 96-well plates to evaluate dose–response relationship and using the epifluorescent microscope set-up to study calcium rise amplitudes and exponential decay kinetics ( Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

“…Such conditions are not human-specific but also affect other mammals such as dogs, cats [ 5 ], and rodents [ 1 ]. Among congenital myasthenic conditions, the group caused by dominant gain-of-function mutations, called slow-channel myasthenic syndromes (SCCMSs), attracted previously our attention [ 6 , 7 ]. SCCMS have long history in translational medicine research.…”

Section: Introductionmentioning

confidence: 99%

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Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

et al. 2021

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Slow-channel congenital myasthenic syndromes (SCCMSs) are rare genetic diseases caused by mutations in muscle nicotinic acetylcholine receptor (nAChR) subunits. Most of the known SCCMS-associated mutations localize at the transmembrane region near the ion pore. Only two SCCMS point mutations are at the extracellular domains near the acetylcholine binding site, α1(G153S) being one of them. In this work, a combination of molecular dynamics, targeted mutagenesis, fluorescent Ca2+ imaging and patch-clamp electrophysiology has been applied to G153S mutant muscle nAChR to investigate the role of hydrogen bonds formed by Ser 153 with C-loop residues near the acetylcholine-binding site. Introduction of L199T mutation to the C-loop in the vicinity of Ser 153 changed hydrogen bonds distribution, decreased acetylcholine potency (EC50 2607 vs. 146 nM) of the double mutant and decay kinetics of acetylcholine-evoked cytoplasmic Ca2+ rise (τ 14.2 ± 0.3 vs. 34.0 ± 0.4 s). These results shed light on molecular mechanisms of nAChR activation-desensitization and on the involvement of such mechanisms in channelopathy genesis.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

et al. 2021

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“…In our recent work on low molecular weight compounds (Kudryavtsev et al, 2018;Spirova et al, 2019), a-conotoxins (Kudryavtsev et al, 2015;Kasheverov et al, 2016;Kryukova et al, 2018a), and human Ly6 proteins (Lyukmanova et al, 2016;Durek et al, 2017), we found that some of them can bind to the orthosteric or allosteric sites of nAChRs. Here we did not plan a detailed investigation of the mechanism of oligoarginine action, but we made exceptions for R8 and W2R4.…”

Section: Discussionmentioning

confidence: 95%

Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors

et al. 2019

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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 acetylcholinebinding protein and ligand-binding domain of the nAChR a9 subunit, we synthesized a series of R3, R6, R8, and R16 oligoarginines and investigated their activity by competition with radioiodinated a-bungarotoxin, two-electrode voltageclamp electrophysiology, and calcium imaging. R6 and longer peptides inhibited muscle-type nAChRs, a7 nAChRs, and a3b2 nAChRs in the micromolar range. The most efficient inhibition of ion currents was detected for muscle nAChR by R16 (IC 50 5 157 nM) and for the a9a10 subtype by R8 and R16 (IC 50 5 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 a9a10 nAChR. For R8, the electrophysiological and competition experiments indicated the existence of two distinct binding sites on a9a10 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.

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“…In 2009, Wang et al [ 81 ] synthesized a marine-derived makaluvamine analog, named 7-(4-fluorobenzylamino)-1,3,4,8-tetrahydropyrrolo[4,3,2-de]quinolin-8(1H)-one (FBA-TPQ). Makaluvamines are produced by marine sponges [ 82 ]. FBA-TPQ showed a dose-dependent cytotoxicity in human PC3 and LNCaP cells, with IC50 of 0.79 μM, 0.42 μM, and TRAMPC1 murine prostate cancer cells, with IC50 of 0.26 μM.…”

Section: Marine Macroorganismsmentioning

confidence: 99%

Marine Natural Products with Activities against Prostate Cancer: Recent Discoveries

Montuori

Hyde

Crea

et al. 2023

IJMS

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Prostate cancer is the most common cancer in men, with over 52,000 new cases diagnosed every year. Diagnostics and early treatment are potentially hindered by variations in screening protocols, still largely reliant on serum levels of acid phosphatase and prostate-specific antigen, with tumour diagnosis and grading relying on histopathological examination. Current treatment interventions vary in terms of efficacy, cost and severity of side effects, and relapse can be aggressive and resistant to the current standard of care. For these reasons, the scientific community is looking for new chemotherapeutic agents. This review reports compounds and extracts derived from marine organisms as a potential source of new drugs against prostate cancer. Whilst there are several marine-derived compounds against other cancers, such as multiple myeloma, leukemia, breast and lung cancer, already available in the market, the presently collated findings show how the marine environment can be considered to hold potential as a new drug source for prostate cancer, as well. This review presents information on compounds presently in clinical trials, as well as new compounds/extracts that may enter trials in the future. We summarise information regarding mechanisms of action and active concentrations.

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

Cited by 8 publications

References 37 publications

Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

Point Mutations of Nicotinic Receptor α1 Subunit Reveal New Molecular Features of G153S Slow-Channel Myasthenia

Oligoarginine Peptides, a New Family of Nicotinic Acetylcholine Receptor Inhibitors

Marine Natural Products with Activities against Prostate Cancer: Recent Discoveries

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