Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
➤ Gửi thông báo lỗi ⚠️ Báo cáo tài liệu vi phạmNội dung chi tiết: Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
ChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1odulation of Voltage-Gated Potassium ChannelsChris Dockendorff, Disha M. Gandhi, Ian H. Kimball, Kenneth s. Eum, Radda Rusinova, Helgi I. Ingolfsson, Ruchi Kapoor, Thasin Peyear, Matthew w. Dodge, Stephen F. Martin, Richard w. Aldrich, Olaf s. Andersen, Jon T. SackSubmitted date: 21/02/2018 Posted d Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1ate: 21/02/2018Licence: cc BY-NC-ND4.0Citation information: Dockendorff. Chris; Gandhi, Disha M.; Kimball, Ian H.; Eum, Kenneth s.; Rusinova, Radda: ISynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
. Ingolfsson. Helgi: et al. (2018): Synthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer PerturbatChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1tein-ligand interactions IS an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT IS a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1making It an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action againstSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, wChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1ork demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported.File list (2)2018 02 20 BrMT analogs.pdf (2.64 MiB)2018 02 20 BrMT analogs Sl.pdf (1.87 MiB)view on ChemRxiv download filev Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1iew on ChemRxiv download fileSynthetic analogs of the snail toxin 6-bromo-2-mercaptotryptamine dimer (BrMT) reveal that lipid bilayer perturbation doeSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
s not underlie its modulation of voltage-gated potassium channels.Chris Dockendorff.*’ Disha M Gandhi.* Ian H. Kiniball? Kenneth s. Enin?! Radda RusinChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1Department of Chemistry. Marquette University. PO Box 1881. Milwaukee. H7. 53201-1881, USA' Department of Physiology Á Membrane Biology. University of California, 1 Shields Arenite, Davis, CA, 95616, USA‘ Department of Neuroscience. University qf Texas at Austin. 1 University Station. Austin. TN. 78 Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1712, USAd Department of Chemistry, University of Texas at Austin, 1 University Station, Austin, TN, 78712, USA'' Department of Physiology and BiophysiSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
cs. Belli Cornell Medical College. New York. NY 10065. USAI Deceased. June 22, 2014■Correwondiaa author. chiUtcpliCTxloekcndorffaiBv etfoi Tel: *1 414ChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1tinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy' for doing so. using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogs. BrMT is a chemically imstable marine snail toxin that ha Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1s unique effects on voltagegated K" channel proteins, making It an attractive medicinal chemistry lead. BrMT is amphiplulic and perturbs lipid bilayerSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
s, raising the question of whether its action against K* channels is merely a manifestation of membrane perturbation. To determine whether medicinal cChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1* channel activity and lipid bilayer properties. Our work demonstrates a strategy for determining if drugs act by specific interactions or brlayer-dependent mechanisms, and chemically stable modulators ofKvl channels are reported.INTRODUCTIONBiological membranes are composites of lipid bilayers and Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1embedded proteins. It has long been known that membrane protein function is sensitive to the composition of the host bilayer.(/-ự) Commonly, dnigs thaSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
t modulate membrane proteins are presumed to target proteins, while in fact many act by changing the bulk properties of the host bilayer, thereby alteChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1membrane protems.(ố. 7, 9-15) When interpreting the mechanisms underlying the physiological actions of a drug, it thus becomes crucial to determine whether the action of an amphiphilic modulator may involve bulk bilayer perturbation, in addition to more specific interactions.A prominent example of t Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1he importance of understanding drug mechanism involves capsaicin, a natural product of chili peppers that stimulates mammalian peripheral neurons to eSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
voke a sensation of binning heat. Capsaicin perturbs bilayers and modulates a wide variety of membrane proteins, including Na*. K*. and TRP channels. ChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1(70) Medicinal chemistry approaches have been successfill in generating analogs of capsaicin that are selective TRPV1 inliibitoi $.(/■) Similar efforts to selectively modulate Na* or K* channels with capsaicin analogs would be foolhardy, however, because modulation of membrane proteins via bilayer p Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1erturbation is fundamentally promiscuous. Thus, determining if lipid bilayer perturbation underlies modulation of a target is critical for the predictSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
ion of undesúed effects on other membrane proteins.Because lipophilic and amphiphilic drugs, by then chemical nature, partition into membranes and perChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1ing modulation of any particular tar get protein. To identify whether dnigs operate by a bilayer mechanism, we previously developed a method of testing modulators for promiscuous activity against multiple umelated classes of membrane proteins/,7) Although this method is effective, it requires signif Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1icant resources and expertise with many membrane protein preparations Herein we report a greatly simplified strategy for using structure-activity relaSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
tionships (SARs) of a modulator against a single target of interest, in combination with synthetic membrane assays, to dissect the effects of bulk bilChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1c 6-bromo-2-mercaptotiyptamme (BrMT. la). A component of the defensive mucus of the marine snail CoUiostoma Cíinốilicnlíìritm. it inhibits voltage-gated K* channels of the Kvl and Kv4 subfamilies.! IS) BrMT is an allosteric modulator that inhibits channels by slowing the voltage activation steps tha Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1t precede pore opening, without blocking the central channel pore.(79. 20) Allosteric modulators of Kv channels are valuable not only as research toolSynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
s but also potentially as therapeutics. (27. 22) BrMT itself has limited utility because it contains a chemically labile disulfide bond that is degradChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1s suggest that the activity of BrMT against Kv channels may be affected by non-specific membrane partitioning. First, high concentrations of BrMT applied to outside-out membrane patches disnipt the patch-clamp seal.(19) Second, a series of chimeras between the BrMT-sensitive Shaker Kv channel and th Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1e insensitive Kv2.1 channel suggest that the region imparting sensitivity is in the SI. S2. and or S3 transmembrane regions of sensitive cliamrels/23)Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
Third, the wash-in and wash-out kinetics of BrMT are multiphasic. suggesting slow accumulation of B1MT in the cell membrane during prolonged exposureChemRxivSynthetic Analogs of the Snail Toxin 6-Bromo-2-Mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Mo Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1T slows Kv channel voltage activation only when applied from the extracellular side of the membrane.(19) suggesting that Its two positive charges may prevent it from crossing the membrane entirely. Certain Kv modulator peptides from animal venoms partition into, but do not cross, the outer leaflet o Synthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1f the plasma membrane bilayer. Many of these peptides bind to the transmembrane voltage sensor domains of the channels.(25-27) However, other closelySynthetic_Analogs_of_the_Snail_Toxin_6-Bromo-2-Mercaptotryptamine_Dimer__BrMT__Reveal_That_Lipid_Bilayer_Perturbation_Do_v1
related venom peptides modulate ion channels via bilayer perturbation.(25) It remains unclear whether BrMT modulates K* channels by direct channel binGọi ngay
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