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Disulfide Bond As a New Modifiable Site of Α-Conotoxin Txib

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Disulfide Bond As a New Modifiable Site of Α-Conotoxin Txib marine drugs Article Cysteine [2,4] Disulfide Bond as a New Modifiable Site of α-Conotoxin TxIB Baojian Zhang 1 , Maomao Ren 1, Yang Xiong 1, Haonan Li 1, Yong Wu 2, Ying Fu 1, Dongting Zhangsun 1,2, Shuai Dong 1,* and Sulan Luo 1,2,* 1 Key Laboratory of Tropical Biological Resources of Ministry of Education, Key Laboratory for Marine Drugs of Haikou, School of Life and Pharmaceutical Sciences, Hainan University, Haikou 570228, China; [email protected] (B.Z.); [email protected] (M.R.); [email protected] (Y.X.); [email protected] (H.L.); [email protected] (Y.F.); [email protected] (D.Z.) 2 Medical School, Guangxi University, Nanning 530004, China; [email protected] * Correspondence: [email protected] (S.D.); [email protected] (S.L.) Abstract: α-Conotoxin TxIB, a selective antagonist of α6/α3β2β3 nicotinic acetylcholine receptor, could be a potential therapeutic agent for addiction and Parkinson’s disease. As a peptide with a complex pharmacophoric conformation, it is important and difficult to find a modifiable site which can be modified effectively and efficiently without activity loss. In this study, three xylene scaffolds were individually reacted with one pair of the cysteine residues ([1,3] or [2,4]), and iodine oxidation was used to form a disulfide bond between the other pair. Overall, six analogs were synthesized with moderate isolated yields from 55% to 65%, which is four times higher than the traditional two-step oxidation with orthogonal protection on cysteines. The cysteine [2,4] modified analogs, with higher stability in human serum than native TxIB, showed obvious inhibitory effect and selectivity on α6/α3β2β3 nicotinic acetylcholine receptors (nAChRs), which was 100 times more than the cysteine [1,3] modified ones. This result demonstrated that the cysteine [2,4] disulfide bond is a new modifiable site of TxIB, and further modification can be a simple and feasible strategy for the Citation: Zhang, B.; Ren, M.; Xiong, exploitation and utilization of α-Conotoxin TxIB in drug discovery. Y.; Li, H.; Wu, Y.; Fu, Y.; Zhangsun, D.; Dong, S.; Luo, S. Cysteine [2,4] Keywords: α-Conotoxin TxIB; peptidomimetics; disulfide bond; high yield; activity Disulfide Bond as a New Modifiable Site of α-Conotoxin TxIB. Mar. Drugs 2021, 19, 119. https://doi.org/ 10.3390/md19020119 1. Introduction Nicotinic acetylcholine receptors (nAChRs) are one kind of pentameric ligand-gated Received: 5 January 2021 ion channels that are widely expressed in the central and peripheral nervous systems. Sev- Accepted: 16 February 2021 eral nAChRs are involved in pathologies and disorders, and the ligands of these receptors Published: 22 February 2021 may exhibit therapeutic potential [1]. α6-Containing nAChR subtypes are prominently expressed in dopaminergic neurons of the ventral tegmental area and the substantia nigra Publisher’s Note: MDPI stays neutral pars compacta, making them potential targets for Parkinson’s disease, nicotine addiction with regard to jurisdictional claims in and alcohol addiction [2–5]. published maps and institutional affil- α-Conotoxins, which act as competitive nAChRs antagonists, are the most widely iations. studied conotoxins. Preliminary studies have found various α-Conotoxins with good activity and specificity for nAChR subtypes [6]. They have good guiding significance for studying the function and structure of nAChRs and the associated diseases. For example, VnIB is a specific ligand for human α6/α3β4 receptor with an IC50 of 5.3 nM [7], [S9K]TxID Copyright: © 2021 by the authors. has a specificity for mouse α3β4 nAChR [8] and GeXIVA can effectively inhibit α9α10 Licensee MDPI, Basel, Switzerland. nAChR [9]. Recent research has shown that ImI-modified paclitaxel polymeric micelles This article is an open access article can target non-small cell lung cancer tumor cells which overexpressed α7 nAChR [10]. distributed under the terms and α-Conotoxins are cysteine-rich peptides, with disulfide bonds to form the accurate phar- conditions of the Creative Commons macophoric conformation. Disulfide bonds are unstable under reducing conditions, so the Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ strategy of disulfide bond engineering has potential value [11–22]. Presently, there are a 4.0/). variety of strategies employed in conotoxin disulfide bond modification, such as disulfide Mar. Drugs 2021, 19, 119. https://doi.org/10.3390/md19020119 https://www.mdpi.com/journal/marinedrugs Mar. Drugs 2021, 19, x FOR PEER REVIEW 2 of 11 Mar. Drugs 2021, 19, 119 2 of 11 variety of strategies employed in conotoxin disulfide bond modification, such as disulfide bond replacement by thioether, lactam bond, selenoether, selenylsulfide, 1,2,3-triazole, bond replacement by thioether, lactam bond, selenoether, selenylsulfide, 1,2,3-triazole, diselenide and dicarba [23,24]. Disulfide bond replacement by 1,2,3-triazole was studied diselenide and dicarba [23,24]. Disulfide bond replacement by 1,2,3-triazole was studied in conotoxin MrIA and GI. Astrid Knuhtsen et al. found that replacement of the disulfide in conotoxin MrIA and GI. Astrid Knuhtsen et al. found that replacement of the disulfide bond with a triazole group maintained its biological activity, and stability tests in rat bond with a triazole group maintained its biological activity, and stability tests in rat plasma indicated that it significantly improved its plasma half-life by 10-fold compared plasma indicated that it significantly improved its plasma half-life by 10-fold compared with native GI [25,26]. with native GI [25,26]. α-Conotoxin TxIB is the most selective antagonist of rα6/α3β2β3 nAChR with an IC50 α-Conotoxin TxIB is the most selective antagonist of rα6/α3β2β3 nAChR with an of 28.4 nM [27]. It has great therapeutic value for nicotine and alcohol addiction. You et IC50 of 28.4 nM [27]. It has great therapeutic value for nicotine and alcohol addiction. You etal. al.found found that that the the globular globular TxIB TxIB is is an an exce excellentllent antiaddiction antiaddiction drug on nicotine-inducednicotine-induced conditioned placeplace preference preference (NIC-induced (NIC-induced CPP) CPP) [28 [28].]. However, However, as aas polypeptide a polypeptide with with two disulfidetwo disulfide bonds, bonds, TxIB TxIB suffers suffers from from low syntheticlow synthetic yield, yield, poor poor metabolic metabolic stability stability and lowand bioavailabilitylow bioavailabilityin vivo in ,vivo, thus thus affecting affecting its pharmaceutical its pharmaceutical potential. potential. In order In order to prepare to prepare TxIB efficiently,TxIB efficiently, Wu et Wu al. et explored al. explored the free the oxidationfree oxidation of TxIB of TxIB to get to onlyget only the globularthe globular isomer, iso- butmer, the but isolated the isolated yield yield was notwas reported not reported [29]. [29]. Yu et Yu al. et explored al. explored the usethe ofuseEscherichia of Escherichia coli expressioncoli expression to generate to generate TxIB TxIB and getand about get about 3 mg/L 3 mg/L r-TxIB r-TxIB (GCCSDPPCRNKHPDLCM) (GCCSDPPCRNKHPDLCM) with anwith additional an additional Met residue Met residue at its C-terminus,at its C-terminus, which which still showed still showed good selectivity good selectivity to inhibit to ratinhibitα6/ ratα3β α26/βα33 nAChRβ2β3 nAChR [30]. To [30]. increase To increase stability, stability, Li et al. Li used et al. a used normal a normal GGAAGAG GGAAGAG linker tolinker cyclize to cyclize TxIB and TxIB improve and improve its serum its stability serum stability [31]. While [31]. some While of thesome amino of the acid amino residues acid ofresidues natural ofα -Conotoxinnatural α-Conotoxin TxIB have TxIB a reactive have sidea reactive chain, likeside Ser,chain, Asp, like Arg, Ser, Asn, Asp, Lys Arg, and Asn, His, theseLys and reactive His, sidethese chains reactive make side it achains challenge make for it selective a challenge cyclisation for selective and modification. cyclisation Theand yieldmodification. for formation The yield of two for disulfide formation bonds of two by orthogonaldisulfide bonds protection by orthogonal strategy is protection normally aroundstrategy 15% is normally and backbone around cyclization 15% and isbackbone even less, cyclization which increases is even the less, difficulty which andincreases costs substantiallythe difficulty duringand costs research substantially and development. during research and development. Xylene dibromides dibromides are are highly highly reactive reactive linkers linkers used used in inpeptide peptide cyclization cyclization [32]. [ 32In]. this In thisexperiment, experiment, three three xylene xylene dibromide dibromide scaffolds scaffolds (m-, o- (m-, and o- p-xylene and p-xylene dibromide) dibromide) were wereindi- individuallyvidually reacted reacted with withone pair one of pair the cysteine of the cysteine residues residues ([1,3] or ([1,3][2,4]), orand [2,4]), iodine and oxidation iodine oxidationwas used to was form used a disulfide to form abond disulfide between bond the betweenother pair the (Figure other 1). pair This (Figure increased1). This the increasedyield significantly the yield and significantly enhanced and the enhanced serum stability the serum slightly. stability TxIB[2,4]-o, slightly. m, TxIB[2,4]-o, p analogs m, still p analogsshow obvious still show inhibition obvious inhibitionon α6/α3 onβ2βα36/ nAChR,α3β2β3 nAChR,which is which 100 istimes 100 timesmore morethan than the theTxIB[1,3]-m, TxIB[1,3]-m, o, p o,analogs. p analogs. This This will willallow allow guidance guidance for further for further structure structure modification modification and andwill willbe conducive be conducive to the to applicability the applicability of TxIB of TxIB as a asstable, a stable, bioavailable bioavailable probe probe or drug or drug that thatis specific is specific for α for6/αα36/β2αβ3 βnAChR.2β3 nAChR. Figure 1. Six α-Conotoxin TxIB analogs (# signify C-term amidation). 2. Results 2.1. Reaction Condition Optimization and Synthesis of TxIB Analogs 2.1. Reaction Condition Optimization and Synthesis of TxIB Analogs The resin-attached peptide was synthesized by standard Fmoc solid-phase synthesis technology, then cleaved and purified by preparative HPLC.
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