Marine Drugs
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2024
·Vol. 22
·期 9
·390
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IF 4.9
Jinpeng Yu,Junjie Xie,Yuting Ma,Pengcheng Wei,Panpan Zhang,Zepei Tang,Xiaopeng Zhu,Dongting Zhangsun,Sulan Luo
α-Conotoxins are disulfide-rich peptides obtained from the venom of cone snails, which are considered potential molecular probes and drug leads for nAChR-related disorders. However, low specificity towards different nAChR subtypes restricts the further application of many α-conotoxins. In this work, a series of loop1 amino acid-substituted mutants of α-conotoxin RegIIA were synthesized, whose potency and selectivity were evaluated by an electrophysiological approach. The results showed that loop1 alanine scanning mutants [H5A]RegIIA and [P6A]RegIIA blocked rα7 nAChR with IC50s of 446 nM and 459 nM, respectively, while their inhibition against rα3β2 and rα3β4 subtypes was negligible, indicating the importance of the fifth and sixth amino acid residues for RegIIA’s potency and selectivity. Then, second-generation mutants were designed and synthesized, among which the analogues [H5V]RegIIA and [H5S]RegIIA showed significantly improved selectivity and comparable potency towards rα7 nAChR compared with the native RegIIA. Overall, these findings provide deep insights into the structure–activity relationship of RegIIA, as well as revealing a unique perspective for the further modification and optimization of α-conotoxins and other active peptides.
研究领域:
神经科学
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药理学
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分子生物学
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DOI
PubMed
高影响因子
MOLECULES
·
2024
·Vol. 29
·期 5
·1181
·
IF 4.2
Minghe Wang,Zhouyuji Liao,Dongting Zhangsun,Yong Wu,Sulan Luo
Antimicrobial peptides (AMPs), acknowledged as host defense peptides, constitute a category of predominant cationic peptides prevalent in diverse life forms. This study explored the antibacterial activity of α-conotoxin RgIA, and to enhance its stability and efficacy, D-amino acid substitution was employed, resulting in the synthesis of nine RgIA mutant analogs. Results revealed that several modified RgIA mutants displayed inhibitory efficacy against various pathogenic bacteria and fungi, includingCandida tropicalisandEscherichia coli. Mechanistic investigations elucidated that these polypeptides achieved antibacterial effects through the disruption of bacterial cell membranes. The study further assessed the designed peptides’ hemolytic activity, cytotoxicity, and safety. Mutants with antibacterial activity exhibited lower hemolytic activity and cytotoxicity, with Pep 8 demonstrating favorable safety in mice. RgIA mutants incorporating D-amino acids exhibited notable stability and adaptability, sustaining antibacterial properties across diverse environmental conditions. This research underscores the potential of the peptide to advance innovative oral antibiotics, offering a novel approach to address bacterial infections.
研究领域:
药理学
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微生物学
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生物化学
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DOI
PubMed
高影响因子
Marine Drugs
·
2023
·Vol. 21
·期 5
·286
·
IF 5.4
Jianying Dong,Panpan Zhang,Junjie Xie,Ting Xie,Xiaopeng Zhu,Dongting Zhangsun,Jinpeng Yu,Sulan Luo
α4/6-conotoxin TxID, which was identified fromConus textile, simultaneously blocks rat (r) α3β4 and rα6/α3β4 nicotinic acetylcholine receptors (nAChRs) with IC50values of 3.6 nM and 33.9 nM, respectively. In order to identify the effects of loop2 size on the potency of TxID, alanine (Ala) insertion and truncation mutants were designed and synthesized in this study. An electrophysiological assay was used to evaluate the activity of TxID and its loop2-modified mutants. The results showed that the inhibition of 4/7-subfamily mutants [+9A]TxID, [+10A]TxID, [+14A]TxID, and all the 4/5-subfamily mutants against rα3β4 and rα6/α3β4 nAChRs decreased. Overall, ala-insertion or truncation of the 9th, 10th, and 11th amino acid results in a loss of inhibition and the truncation of loop2 has more obvious impacts on its functions. Our findings have strengthened the understanding of α-conotoxin, provided guidance for further modifications, and offered a perspective for future studies on the molecular mechanism of the interaction between α-conotoxins and nAChRs.Keywords:α-conotoxin TxID;α3β4 nAChR;loop size modification;electrophysiology;CD spectra
研究领域:
药理学
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神经科学
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生物化学
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DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2021
·
IF 4.418
Yishuai Yang,Yao Tan,Dongting Zhangsun,Xiaopeng Zhu,Sulan Luo
Nicotinic acetylcholine receptors (nAChRs) are essential pentameric ligand-gated ion channels that are distributed throughout the central and peripheral nervous systems and non-neuronal tissues in mammalian species that play critical roles in a variety of neural and mental activities. The α3β2 nAChR subtype participates in pain, addiction to nicotine, and other neurophysiological and pathological activities. Owing to the lack of highly selective pharmacological tools targeting α3β2, related research on its tissue distribution and function has been hindered. α-Conotoxin (α-CTx) LtIA, discovered from Conus literatus in our lab, potently and selectively blocks α3β2 nAChR, providing an important molecular probe to study the α3β2 nAChR structure and function. We used the fluorescent molecule 5-carboxytetramethylrhodamine succinimidyl ester, which can react with the N-terminus of LtIA, to obtain a novel fluorescent analogue of LtIA (LtIA-F). The potency and selectivity of LtIA-F were tested using a two-electrode voltage clamp recording on various nAChRs expressed in Xenopus laevis oocytes. LtIA-F potently inhibited ACh-evoked currents at the α3β2 nAChR, with an IC50 value of 90.66 nM, displaying a ∼4-fold decrease in potency compared with native LtIA without a change in selectivity. The serum stability results indicated that LtIA-F exhibited stability similar to that of native LtIA. This study on an α-CTx LtIA fluorescent analogue provides a wealth of pharmacological tools to explore the structure–function relationship, distribution, and ligand binding domain of the α3β2 nAChR subtype.
研究领域:
神经生物学
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药理学
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DOI
PubMed
高影响因子
Marine Drugs
·
2025
·Vol. 23
·期 4
·161
·
IF 5.4
Rongyan He,Mingjuan Li,Weitao Li,Wenqi Li,Shuting Xiao,Qiuyu Cao,Huanbai Wang,Dongting Zhangsun,Sulan Luo
Chronic neuropathic pain severely impairs quality of life, with current therapies often causing adverse effects. Our research group identified αO-conotoxin GeXIVA[1,2] as a potent analgesic candidate derived from marine cone snails. However, its clinical application is limited by rapid clearance and complex administration. This study developed a sustained-release hydrogel microneedle patch encapsulating GeXIVA[1,2] to address these challenges. Optimized 4:3 (w/w) polyvinyl alcohol (PVA)–sucrose hydrogel formulation achieved 98.6% structural integrity and controlled swelling (ratio = 1.9 at 48 h). The microneedles demonstrated uniform conical morphology (height: 889 ± 49 µm, base: 381 ± 26 µm) enabling epidermal penetration. In spared nerve injury (SNI) models, a single microneedle patch application increased mechanical paw withdrawal thresholds from 0.056 g to 0.7269 g, maintaining efficacy for 3 days. Chronic constriction injury (CCI) models showed comparable pain relief. Notably, microneedle patch treatment improved locomotor function in SNI mice (total movement: 1518 cm vs. 1126 cm untreated). This hydrogel microneedle patch platform extends GeXIVA[1,2]’s analgesic duration from hours to days through sustained release, while resolving administration challenges through transdermal delivery, expanding the potential applications of GeXIVA[1,2], and demonstrating a promising strategy for the chronic neuropathic pain management.
研究领域:
药理学
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疼痛管理
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生物材料科学
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DOI
PubMed
高影响因子
Marine Drugs
·
2021
·Vol. 19
·期 2
·119
·
IF 5.118
Baojian Zhang,Maomao Ren,Yang Xiong,Haonan Li,Yong Wu,Ying Fu,Dongting Zhangsun,Shuai Dong,Sulan Luo
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 exploitation and utilization of α-Conotoxin TxIB in drug discovery.
研究领域:
药理学
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神经科学
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药物化学
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DOI
高影响因子
Applied Materials Today
·
2021
·
IF 10.041
Xinlian Zhao,Lulu Jin,Zhixin Zhu,Haohao Lu,Haifei Shi,Qi Zhong,Joaquim Miguel Oliveira,Rui L. Reis,Changyou Gao,Zhengwei Mao
Spinal cord injury (SCI) is a severe refractory disabling condition accompanied by complicated pathological processes, such as excessive glutamate release in the extracellular environment and massive influx of Ca 2+ into cells. Dextran can absorb extracellular glutamate and Ca 2+ to attenuate persistent excitatory processes that are detrimental to normal cells. Calcium channel inhibitors reduce the influx of Ca 2+ , thereby relieving subsequent cytotoxicity such as mitochondria damage. Here, a bifunctional microgel was designed for delivering GVIA, an N-type calcium ion channel blocker, to achieve a combinational therapy of simultaneously reducing the Ca 2+ and glutamate concentrations in extracellular environment and inhibiting excess Ca 2+ influx. The obtained dextran microgels could effectively encapsulate GVIA peptide, which displayed sustained release. Microgels loaded with GVIA (DexGVIA) played an excellent neuroprotective role by relieving the influx of Ca 2+ in vitro . DexGVIA also exhibited promising therapeutic effect in vivo via reducing the lesion cavity, saving neurons and gliacytes from the injury, and improving continuity and integrity of the spinal cord, thus distinctly accelerated motor functional recovery of SCI rats. Our work provided a combinational strategy against excitotoxicity, with potential applications not only in SCI, but also in other pathologically similar conditions of the central nervous system.
研究领域:
神经科学
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药学
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生物医学工程
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DOI
高影响因子
Marine Drugs
·
2024
·
IF 4.9
Xin Sun,Jiangnan Hu,Maomao Ren,Hong Chang,Dongting Zhangsun,Baojian Zhang,Shuai Dong
α-Conotoxins, as selective nAChR antagonists, can be valuable tools for targeted drug delivery and fluorescent labeling, while conotoxin-drug or conotoxin-fluorescent conjugates through the disulfide bond are rarely reported. Herein, we demonstrate the [2,4] disulfide bond of α-conotoxin as a feasible new chemical modification site. In this study, analogs of the α-conotoxin LsIA cysteine[2,4] were synthesized by stapling with five linkers, and their inhibitory activities against human α7 and rat α3β2 nAChRs were maintained. To further apply this method in targeted delivery, the alkynylbenzyl bromide linker was synthesized and conjugated with Coumarin 120 (AMC) and Camptothecin (CPT) by copper-catalyzed click chemistry, and then stapled between cysteine[2,4] of the LsIA to construct a fluorescent probe and two peptide-drug conjugates. The maximum emission wavelength of the LsIA fluorescent probe was 402.2 nm, which was essentially unchanged compared with AMC. The cytotoxic activity of the LsIA peptide-drug conjugates on human A549 was maintained in vitro. The results demonstrate that the stapling of cysteine[2,4] with alkynylbenzyl bromide is a simple and feasible strategy for the exploitation and utilization of the α-conotoxin LsIA.
研究领域:
药物化学
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生物化学
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分子生物学
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药物递送系统
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产品关联
DOI
PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Chenxing Xu,Nan Wang,Tao Ma,Shengrong Pei,Meiting Wang,Jinpeng Yu,Dongting Zhangsun,Xiaopeng Zhu,Sulan Luo
α 3 β 4, a vital subtype of neuronal nicotinic acetylcholine receptors (nAChRs), is widely distributed in the brain, ganglia, and adrenal glands, associated with addiction and neurological diseases. However, the lack of specific imaging tools for α 3 β 4 nAChRs has hindered the investigation of their tissue distribution and functions. [D11A]LvIA, a peptide derived from marine cone snails, demonstrates high affinity and potency for α 3 β 4 nAChRs, making it a valuable pharmacological tool for studying this receptor subtype. In this study, three fluorescent conjugates of [D11A]LvIA were synthesized using 6-TAMRA-SE (R), Cy3-NHS-ester (Cy3), and BODIPY-FL NHS ester (BDP) dyes. The electrophysiological activities were assessed in Xenopus laevis oocytes by two-electrodes voltage clamp (TEVC). [D11A]LvIA-Cy3 and [D11A]LvIA-BDP show improved selectivity and affinity, with IC 50 values of 512.70 nM and 343.50 nM, respectively, and [D11A]LvIA-Cy3 exhibits better stability in cerebrospinal fluid. Utilizing [D11A]LvIA-Cy3, we successfully visualized the distribution of α 3 β 4 nAChRs in rat trigeminal ganglia, retina, adrenal glands, and various brain regions. This novel fluorescent peptide provides a significant pharmacological tool for the exploration and visualization in-situ distribution of α 3 β 4 nAChRs in different tissues and also assists in clarifying the function.
研究领域:
神经科学
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药理学
·
成像技术
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）