Review

Targeting Acid-Sensing Ion Channels with Toxin Peptides: Analgesic Mechanisms and Biosynthesis Development

  • 李海婷 ,
  • 吴小余 ,
  • 曹春阳
Expand
  • a(College of Science, Shanghai University, Shanghai 200444)
    b(State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032)

Received date: 2025-04-03

  Online published: 2025-06-04

Supported by

Strategic Priority Research Program of the Chinese Academy of sciences grant (XDB1060000)

Abstract

Acid-sensing ion channels (ASICs), as proton-gated cation channels, play critical roles in acidosis-evoked pain signaling through their subtype-specific contributions to nociceptive pathways. ASIC1a predominantly drives central sensitization in neuropathic pain, while ASIC3 mediates peripheral inflammatory and musculoskeletal pain. While conventional analgesics, such as opioids and nonsteroidal antiinflammatory drugs, are limited by central side effects and poor selectivity, natural toxin peptides demonstrate remarkable therapeutic potential. PcTx1 (from tarantula venom), Mambalgin (snake-derived), and APETx2 (sea anemone toxin) exhibit nanomolar affinity for ASIC extracellular domains, effectively modulating channel gating to achieve potent analgesia without addiction risks. This review systematically elucidates the molecular architecture and gating mechanisms of ASICs, providing in-depth analysis of representative toxin peptides' mechanisms towards ASICs. PcTx1 stabilizes ASIC1a in a desensitized state through acidic pocket engagement, while Mambalgin-1 locks the thumb domain in resting state to inhibit activation. APETx2 is proposed to block ASIC3 via a basic amino acid cluster binding to the site between palm and wrist domain, as suggested by homology modeling. Biosynthetic strategies have advanced significantly, with Escherichia coli serving as a cost-effective platform for rapid production of disulfide-rich peptides through engineered oxidative folding pathways (e.g., DisCoTune system). Pichia pastoris enables secretory expression with low immunogenicity by post-translational modification systems and α-mating factor signals. For complex modifications, mammalian cells (e.g., chinese hamster ovary cells) provide precise folding and human-like post-translational processing. Key optimizations include solubility-enhancing tags (MBP, SUMO), affinity tags (poly-His), and chemical modification like PEGylation to improve pharmacokinetics of toxin peptides. Finally, the discussion extends to challenges in clinical translation of toxin peptide drugs, including incomplete ASIC subtype structural resolution and off-target effects. AI-driven design (AlphaFold2-predicted models) and stimuli-responsive nanocarriers (lipid-based systems) may address these limitations. With interdisciplinary advancements and cross-application of technologies, toxin peptides demonstrate promising potential to overcome limitations of conventional analgesic therapies.

Cite this article

李海婷 , 吴小余 , 曹春阳 . Targeting Acid-Sensing Ion Channels with Toxin Peptides: Analgesic Mechanisms and Biosynthesis Development[J]. Acta Chimica Sinica, 2025 : 25040105 -25040105 . DOI: 10.6023/A25040105

References

[1] Fan B.F.China Pain Medicine Development Report (2020), Tsinghua University Press, Beijing, 2020, Chapter 1.1 (in Chinese).
(樊碧发, 中国疼痛医学发展报告(2020), 清华大学出版社, 北京, 2020, 章节1.1.)
[2] Fürst S.; Zádori Z.S.; Zádor F.; Király K.; Balogh M.; László S.B.; Hutka B.; Mohammadzadeh A.; Calabrese C.; Galambos A.R.; Riba P.; Romualdi P.; Benyhe S.; Timár J.; Schmidhammer H.; Spetea M.; Al-Khrasani M. Molecules2020, 25 (11), 2473.
[3] Provisional Drug Overdose Death Counts; The Centers for Disease Control and Prevention,2025. https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm. (accessed 2025-05-21).
[4] Bindu S.; Mazumder S.; Bandyopadhyay U. Biochem. Pharmacol.2020, 180, 114147.
[5] Waldmann R.; Champigny G.; Bassilana F.; Heurteaux C.; Lazdunski M. Nature1997, 386 (6621), 173-177.
[6] Carnally S.M.; Dev H.S.; Stewart A.P.; Barrera N.P.; Van Bemmelen M.X.; Schild L.; Henderson R.M.; Edwardson, J.M. Biochem. Biophys. Res. Commun.2008, 372 (4), 752-755.
[7] Jasti J.; Furukawa H.; Gonzales E.B.; Gouaux E. Nature2007, 449 (7160), 316-323.
[8] Lingueglia E.; de Weille J.R.; Bassilana F.; Heurteaux C.; Sakai H.; Waldmann R.; Lazdunski, M. J Biol Chem1997, 272 (47), 29778-29783.
[9] Akopian A.N.; Chen C.C.; Ding Y.; Cesare P.; Wood J.N. Neuroreport2000, 11 (10), 2217-2222.
[10] Walder R.Y.; Rasmussen L.A.; Rainier J.D.; Light A.R.; Wemmie J.A.; Sluka K.A. J Pain2010, 11 (3), 210-218.
[11] De Logu F.; Geppetti, P. Handb. Exp. Pharmacol.2019, 260, 161-186.
[12] Schmidtko A.; Lötsch J.; Freynhagen R.; Geisslinger G. Lancet2010, 375 (9725), 1569-1577.
[13] Escoubas P.; De Weille J.R.; Lecoq A.; Diochot S.; Waldmann R.; Champigny G.; Moinier D.; Ménez A.; Lazdunski, M. J Biol Chem2000, 275 (33), 25116-25121.
[14] Diochot S.; Baron A.; Salinas M.; Douguet D.; Scarzello S.; Dabert-Gay A.-S.; Debayle D.; Friend V.; Alloui A.; Lazdunski M.; Lingueglia E. Nature2012, 490 (7421), 552-555.
[15] Diochot S.; Baron A.; Rash L.D.; Deval E.; Escoubas P.; Scarzello S.; Salinas M.; Lazdunski M. EMBO J2004, 23 (7), 1516-1525.
[16] Izumi M.; Ikeuchi M.; Ji Q.; Tani, T. J. Biomed. Sci.2012, 19 (1), 77.
[17] Holton C.M.; Strother L.C.; Dripps I.; Pradhan A.A.; Goadsby P.J.; Holland, P.R. Br. J. Pharmacol.2020, 177 (11), 2478-2486.
[18] Jensen J.E.; Durek T.; Alewood P.F.; Adams D.J.; King G.F.; Rash L.D. Toxicon2009, 54 (1), 56-61.
[19] Schroeder C.I.; Rash L.D.; Vila-Farrés X.; Rosengren K.J.; Mobli M.; King G.F.; Alewood P.F.; Craik D.J.; Durek, T. Angew Chem Int Ed Engl2014, 53 (4), 1017-1020.
[20] Zhang W.J.; Zhang F.J.; Zhao S.F.; Dong Y.X.; Guo K.; Ji, S.L. J. Binzhou Med. Univ.2024, 47 (2), 94-101 (in Chinese).
(张文杰, 张发进, 赵仕法, 董玉香, 郭凯, 姬胜利. 滨州医学院学报 2024, 47 (2), 94-101.)
[21] Peng W.; Cheng R.; Liu H.; Liu D.M.; Su, X.B. Chin. J. Org. Chem.2024, 44 (9), 2876-2888 (in Chinese).
(彭伟, 程蓉, 刘豪, 刘冬梅, 苏贤斌. 有机化学 2024, 44 (9), 2876-2888.)
[22] Yu G.; Zou S.; Zheng J.S. Chembiochem2024, 25 (24), e202400674.
[23] Wang J.Y.; Dong L.Y.; Liu Y.N.; Chen X.T.; Ma Y.N.; Yin H.; Du S.S.; Qi Y.K.; Wang, K.W. Chin. J. Org. Chem.2021, 41 (7), 2800-2809 (in Chinese).
(王金艳, 董黎颖, 刘雅妮, 陈西同, 马艳楠, 尹昊, 杜姗姗, 齐昀坤, 王克威.有机化学. 2021, 41 (7), 2800-2809.)
[24] Yin H.; Chen X.T.; Fu X.Y.; Ma Y.N.; Xu Y.M.; Zhang T.; Liang S.; Du S.S.; Qi Y.K.; Wang, K.W. Acta Chim. Sinica2022, 80 (4), 444-452 (in Chinese).
(尹昊, 陈西同, 付邢言, 马艳楠, 徐以梅, 张特, 梁帅, 杜姗姗, 齐昀坤, 王克威. 化学学报 2022, 80 (4), 444-452.)
[25] Ma Y.; Liu Y.; Wang J.; Chen X.; Yin H.; Chi Q.; Jia S.; Du S.; Qi Y.; Wang K. Chinese Journal of Organic Chemistry2022, 42 (2), 498.
[26] Ho T.Nt.; Tran T.H.; Le H.S.; Lewis, R.J. European Journal of Medicinal Chemistry2025, 282, 117038.
[27] National Medical Products Administration, Drugs. https://www.nmpa.gov.cn/datasearch/home-index.html#category=yp (accessed 2025-05-21). (in Chinese).
(国家药品监督管理局, 药品查询. https://www.nmpa.gov.cn/datasearch/home-index.html#category=yp 访问于2025-05-21)
[28] US Food and Drug Administration. https://www.accessdata.fda.gov/scripts/cder/daf/ (accessed 2025-05-21).
[29] US National Library of Medicine. https://clinicaltrials.gov/ (accessed2025-05-21).
[30] Bordon K. de C.F.; Cologna C.T.; Fornari-Baldo E.C.; Pinheiro-Júnior E.L.; Cerni F.A.; Amorim F.G.; Anjolette F.A.P.; Cordeiro F.A.; Wiezel G.A.; Cardoso I.A.; Ferreira I.G.; de Oliveira I.S.; Boldrini-França J.; Pucca M.B.; Baldo M.A.; Arantes E.C. Front. Pharmacol.2020, 11, 1132.
[31] Anangi R.; Rash L.D.; Mobli M.; King G.F. Mar. Drugs2012, 10 (12), 1605-1618.
[32] Saez N.J.; Cristofori-Armstrong B.; Anangi R.; King, G.F. A Strategy for Production of Correctly Folded Disulfide-Rich Peptides in the Periplasm of E. Coli. In Heterologous Gene Expression in E.coli; Burgess-Brown, N. A., Ed.; Methods in Molecular Biology; Springer New York: New York, NY,2017; Vol. 1586, pp 155-180.
[33] Xu J.; Lei X.; Li A.; Li J.; Li S.; Chen, L. Microb. Cell Fact.2024, 23 (1), 48.
[34] Yin, S.J.; Xiao, M.; Xiang, Q.L.; Li, Y.Y.; Liu, K.Y.; Zhao, Q.R. J. South-Central Minzu Univ. (Nat. Sci. Ed.) 2023, 42 (3), 313-318 (in Chinese).
(尹世金, 肖敏, 向琪琳, 李昱烨, 刘柯驿, 赵倩茹. 中南民族大学学报(自然科学版) 2023, 42 (3), 313-318.)
[35] Yan S.; Tang X.C.; Yu D.M.; Wang H.Y.; Meng W.W.; Tang P.P.; Wang, X.C. Chin. J. Biotechnol.2021, 37 (2), 635-645 (in Chinese).
(颜帅, 唐小超, 余典梅, 王海燕, 孟雯雯, 唐萍萍, 王贤纯. 生物工程学报 2021, 37 (2), 635-645.)
[36] Long, S.R.; Li, Z.Y.; Zhou, Y.X.; Zhao, Q.R.; Li, Y.; Zhang, X.; Yin, S.J. J. Xuzhou Inst. Technol. (Nat. Sci. Ed.) 2021, 36 (1), 86-92 (in Chinese).
(龙思如, 李子怡, 周雨璇, 赵倩茹, 李奕, 张旭, 尹世金. 徐州工程学院学报(自然科学版) 2021, 36 (1), 86-92.)
[37] Mastropietro G.; Aw R.; Polizzi K.M. Methods Enzymol.2021, 660, 53-80.
[38] Anangi R.; Chen C.C.; Lin Y.W.; Cheng Y.R.; Cheng C.H.; Chen Y.C.; Chu Y.P.; Chuang W.J. Toxicon2010, 56 (8), 1388-1397.
[39] Jiang L.P.; Zhang J.; Li X.Y.; Tang, Y.Q. J. Pathog. Biol.2016, 11 (7), 603-606 (in Chinese).
(蒋立平, 章洁, 李先耀, 唐雅琴. 中国病原生物学杂志 2016, 11 (7), 603-606.)
[40] Zhu W.H.; Zhang W.; Xu J.J.; Li Y.; Zhang H.; Wang H.Y. Biotechnol. Bull.2017, 27 (3), 239-244 (in Chinese).
(朱文赫, 张巍, 徐俊杰, 李妍, 张红, 王会岩. 生物技术 2017, 27 (3), 239-244.)
[41] Escoubas P.; Bernard C.; Lambeau G.; Lazdunski M.; Darbon H. Protein Sci2003, 12 (7), 1332-1343.
[42] Tihanyi B.; Nyitray, L. Drug Discovery Today: Technol.2020, 38, 25-34.
[43] Schuhmacher L.-N.; Srivats S.; Smith E.S.J. Mol. Pharmacol.2015, 87 (4), 561-571.
[44] Verkest C.; Salinas M.; Diochot S.; Deval E.; Lingueglia E.; Baron A. Toxins2022, 14 (10), 709.
[45] Rook M.L.; Williamson A.; Lueck J.D.; Musgaard M.; Maclean D.M. eLife2020, 9, e51111.
[46] Rook M.L.; Ananchenko A.; Musgaard M.; MacLean, D.M. Front. Cell. Neurosci.2021, 15, 761813.
[47] Yoder N.; Gouaux E. eLife2020, 9, e56527.
[48] Wu Y.; Chen Z.; Sigworth F.J.; Canessa C.M. Elife2021, 10, e67115.
[49] Yoder N.; Yoshioka C.; Gouaux E. Nature2018, 555 (7696), 397-401.
[50] Baconguis I.; Bohlen C.J.; Goehring A.; Julius D.; Gouaux E. Cell2014, 156 (4), 717-729.
[51] Yoder N.; Gouaux E. PLoS One2018, 13 (8), e0202134.
[52] Gonzales E.B.; Kawate T.; Gouaux E. Nature2009, 460 (7255), 599-604.
[53] Li T.; Yang Y.; Canessa, C.M. J Biol Chem2010, 285 (41), 31285-31291.
[54] Wu Y.; Chen Z.; Canessa C.M. Elife2019, 8, e45851.
[55] Delaunay A.; Gasull X.; Salinas M.; Noël J.; Friend V.; Lingueglia E.; Deval, E. Proc. Natl. Acad. Sci. U.S.A.2012, 109 (32), 13124-13129.
[56] Springauf A.; Bresenitz P.; Gründer, S. J Biol Chem2011, 286 (27), 24374-24384.
[57] Hoagland E.N.; Sherwood T.W.; Lee K.G.; Walker C.J.; Askwith, C.C. J Biol Chem2010, 285 (53), 41852-41862.
[58] Grifoni S.C.; Jernigan N.L.; Hamilton G.; Drummond H.A. Microvasc. Res.2008, 75 (2), 202-210.
[59] Atmani, K.; Meleine, M.; Langlois, L.; Coëffier, M.; Brumovsky, P.; Leroi, A.-M.; Gourcerol, G. Front Pain Res (Lausanne) 2023, 4, 1083514.
[60] Page A.J.; Brierley S.M.; Martin C.M.; Price M.P.; Symonds E.; Butler R.; Wemmie J.A.; Blackshaw L.A. Gut2005, 54 (10), 1408-1415.
[61] Hughes P.A.; Brierley S.M.; Young R.L.; Blackshaw, L.A. J Comp Neurol2007, 500 (5), 863-875.
[62] Wu J.; Xu Y.; Jiang Y.-Q.; Xu J.; Hu Y.; Zha X. Mol. Brain.2016, 9, 4.
[63] Wemmie J.A.; Askwith C.C.; Lamani E.; Cassell M.D.; Freeman J.H.; Welsh M.J. J Neurosci2003, 23 (13), 5496-5502.
[64] Lin S.-H.; Sun W.-H.; Chen C.-C. Neuropharmacology2015, 94, 99-118.
[65] Han D.-S.; Lee C.-H.; Shieh Y.-D.; Chang C.-T.; Li M.-H.; Chu Y.-C.; Wang J.-L.; Chang K.-V.; Lin S.-H.; Chen C.-C. Pain2022, 163 (5), e622-e633.
[66] Gregory N.S.; Gautam M.; Benson C.J.; Sluka K.A. Neuroscience2018, 386, 166-174.
[67] Homma Y.; Nomiya A.; Tagaya M.; Oyama T.; Takagaki K.; Nishimatsu H.; Igawa Y. J Urol2013, 190 (5), 1925-1931.
[68] Cristofori-Armstrong B.; Budusan E.; Rash, L.D. Proc Natl Acad Sci U S A2021, 118 (8), e2021581118.
[69] Jiang Q.; Zha X.-M.; Chu, X.-P. Int J Physiol Pathophysiol Pharmacol2012, 4 (2), 84-93.
[70] Askwith C.C.; Wemmie J.A.; Price M.P.; Rokhlina T.; Welsh, M.J. J Biol Chem2004, 279 (18), 18296-18305.
[71] Jiang N.; Wu J.; Leng T.; Yang T.; Zhou Y.; Jiang Q.; Wang B.; Hu Y.; Ji Y.-H.; Simon R.P.; Chu X.-P.; Xiong Z.-G.; Zha, X.-M. J Cereb Blood Flow Metab2017, 37 (2), 528-540.
[72] Fila M.; Sassi A.; Brideau G.; Cheval L.; Morla L.; Houillier P.; Walter C.; Gennaoui M.; Collignon L.; Keck M.; Planelles G.; Bakouh N.; Peuchmaur M.; Deschênes G.; Anegon I.; Remy S.; Vogt B.; Crambert G.; Doucet A. JCI Insight2021, 6 (15), e148588.
[73] Deval, E.; Salinas, M.; Baron, A.; Lingueglia, E.; Lazdunski, M. J Biol Chem 2004, 279 (19), 19531-19539.
[74] Montaño J.A.; Calavia M.G.; García-Suárez O.; Suarez-Quintanilla J.A.; Gálvez A.; Pérez-Piñera P.; Cobo J.; Vega J.A. Neurosci. Lett.2009, 463 (2), 114-118.
[75] Cabo R.; Gálvez M.A.; San José I.; Laurà R.; López-Muñiz A.; García-Suárez O.; Cobo T.; Insausti R.; Vega J.A. Neurosci. Lett.2012, 516 (2), 197-201.
[76] Sluka K.A.; Gregory N.S. Neuropharmacology2015, 94, 58-63.
[77] Lin S.-H.; Cheng Y.-R.; Banks R.W.; Min M.-Y.; Bewick G.S.; Chen C.-C. Nat. Commun.2016, 7, 11460.
[78] Peng Z.; Li W.-G.; Huang C.; Jiang Y.-M.; Wang X.; Zhu M.X.; Cheng X.; Xu T.-L. Cell Rep.2015, 13 (2), 387-398.
[79] Lee C.-H.; Lin J.-H.; Lin S.-H.; Chang C.-T.; Wu Y.-W.; Bewick G.; Banks R.W.; Gründer S.; Hochgeschwender U.; Chen C.-C. Sci. Adv.2025, 11 (5), eabc5219.
[80] Cheng Y.-R.; Jiang B.-Y.; Chen, C.-C. J. Biomed. Sci.2018, 25 (1), 46.
[81] Hung C.-H.; Chin Y.; Fong Y.-O.; Lee C.-H.; Han D.-S.; Lin J.-H.; Sun W.-H.; Chen C.-C. Pharmacol. Ther.2023, 247, 108444.
[82] Donier E.; Rugiero F.; Jacob C.; Wood, J.N. Eur J Neurosci2008, 28 (1), 74-86.
[83] Hoshikawa M.; Kato A.; Hojo H.; Shibata Y.; Kumamoto N.; Watanabe M.; Ugawa S. Neurosci. Lett.2017, 651, 57-64.
[84] Deval E.; Noël J.; Lay N.; Alloui A.; Diochot S.; Friend V.; Jodar M.; Lazdunski M.; Lingueglia E. EMBO J2008, 27 (22), 3047-3055.
[85] Holton C.M.; Strother L.C.; Dripps I.; Pradhan A.A.; Goadsby P.J.; Holland, P.R. Br. J. Pharmacol.2020, 177 (11), 2478-2486.
[86] Kang Y.Q.; Chen K.; He X.H.; Yin H.; Mao L.W.; Lu Z.N.; Xiao, Z.M. Neural Inj. Funct. Reconstr.2016, 11 (1), 5-8 (in Chinese).
(康玉琪, 陈康, 何小华, 尹皓, 毛立武, 卢祖能, 肖哲曼. 神经损伤与功能重建 2016, 11 (1), 5-8.)
[87] Diochot S.; Alloui A.; Rodrigues P.; Dauvois M.; Friend V.; Aissouni Y.; Eschalier A.; Lingueglia E.; Baron A. Pain2016, 157 (3), 552-559.
[88] Matricon J.; Gelot A.; Etienne M.; Lazdunski M.; Muller E.; Ardid, D. Eur J Pain2011, 15 (4), 335-343.
[89] Diochot S.; Baron A.; Salinas M.; Douguet D.; Scarzello S.; Dabert-Gay A.-S.; Debayle D.; Friend V.; Alloui A.; Lazdunski M.; Lingueglia E. Nature2012, 490 (7421), 552-555.
[90] Nagakura Y.; Oe T.; Aoki T.; Matsuoka N. Pain2009, 146 (1-2), 26-33.
[91] Sugimura N.; Ikeuchi M.; Izumi M.; Kawano T.; Aso K.; Kato T.; Ushida T.; Yokoyama M.; Tani, T. Eur J Pain2015, 19 (5), 629-638.
[92] Xu C.; Gu Y.; Shi Y.T.; Wang G.X.; Niu, X.P. J. Shenyang Med. Coll.2023, 25 (1), 19-23+29 (in Chinese).
(许草, 顾勇, 石亚婷, 汪桂祥, 牛小平. 沈阳医学院学报2023, 25 (1), 19-23+29.)
[93] Chassagnon I.R.; McCarthy C.A.; Chin Y.K.-Y.; Pineda S.S.; Keramidas A.; Mobli M.; Pham V.; De Silva T.M.; Lynch J.W.; Widdop R.E.; Rash L.D.; King, G.F. Proc. Natl. Acad. Sci.2017, 114 (14), 3750-3755.
[94] Budusan E.Biochem. Pharmacol. 2024.
[95] Osmakov D.I.; Kozlov S.A.; Andreev Y.A.; Koshelev S.G.; Sanamyan N.P.; Sanamyan K.E.; Dyachenko I.A.; Bondarenko D.A.; Murashev A.N.; Mineev K.S.; Arseniev A.S.; Grishin, E.V. J Biol Chem2013, 288 (32), 23116-23127.
[96] Kozlov S.A.; Osmakov D.I.; Andreev I.A.; Koshelev S.G.; Gladkikh I.N.; Monastyrnaia M.M.; Kozlovskaia E.P.; Grishin E.V. Bioorg. Khim.2012, 38 (6), 653-659.
[97] Possani L.D.; Merino E.; Corona M.; Bolivar F.; Becerril B. Biochimie2000, 82 (9-10), 861-868.
[98] Pallaghy P.K.; Nielsen K.J.; Craik D.J.; Norton R.S. Protein Sci1994, 3 (10), 1833-1839.
[99] Norton R.S.; Pallaghy P.K. Toxicon1998, 36 (11), 1573-1583.
[100] Saez N.J.; Mobli M.; Bieri M.; Chassagnon I.R.; Malde A.K.; Gamsjaeger R.; Mark A.E.; Gooley P.R.; Rash L.D.; King G.F. Mol. Pharmacol.2011, 80 (5), 796-808.
[101] Baron A.; Diochot S.; Salinas M.; Deval E.; Noël J.; Lingueglia E. Toxicon2013, 75, 187-204.
[102] Kini R.M.; Doley R. Toxicon2010, 56 (6), 855-867.
[103] Mourier G.; Salinas M.; Kessler P.; Stura E.A.; Leblanc M.; Tepshi L.; Besson T.; Diochot S.; Baron A.; Douguet D.; Lingueglia E.; Servent, D. J Biol Chem2016, 291 (6), 2616-2629.
[104] Chagot B.; Escoubas P.; Diochot S.; Bernard C.; Lazdunski M.; Darbon H. Protein Sci2005, 14 (8), 2003-2010.
[105] Jensen J.E.; Cristofori-Armstrong B.; Anangi R.; Rosengren K.J.; Lau C.H.Y.; Mobli M.; Brust A.; Alewood P.F.; King G.F.; Rash, L.D. J. Med. Chem.2014, 57 (21), 9195-9203.
[106] Cristofori-Armstrong B.; Saez N.J.; Chassagnon I.R.; King G.F.; Rash L.D. Biochem Pharmacol2019, 163, 381-390.
[107] Chen X.; Kalbacher H.; Gründer, S. J Gen Physiol2005, 126 (1), 71-79.
[108] Sherwood T.W.; Lee K.G.; Gormley M.G.; Askwith C.C. J Neurosci2011, 31 (26), 9723-9734.
[109] Chen X.; Kalbacher H.; Gründer, S. J Gen Physiol2006, 127 (3), 267-276.
[110] Hoagland E.N.; Sherwood T.W.; Lee K.G.; Walker C.J.; Askwith, C.C. J Biol Chem2010, 285 (53), 41852-41862.
[111] Dawson R.J.P.; Benz J.; Stohler P.; Tetaz T.; Joseph C.; Huber S.; Schmid G.; Hügin D.; Pflimlin P.; Trube G.; Rudolph M.G.; Hennig M.; Ruf A. Nat. Commun.2012, 3, 936.
[112] Liu Y.; Hagan R.; Schoellerman J. Sci. Rep.2018, 8 (1), 7179.
[113] Baconguis I.; Gouaux E. Nature2012, 489 (7416), 400-405.
[114] Cristofori-Armstrong B.; Budusan E.; Rash, L.D. Proc. Natl. Acad. Sci.2021, 118 (8), e2021581118.
[115] Sun D.; Liu S.; Li S.; Zhang M.; Yang F.; Wen M.; Shi P.; Wang T.; Pan M.; Chang S.; Zhang X.; Zhang L.; Tian C.; Liu L. eLife2020, 9, e57096.
[116] Besson T.; Lingueglia E.; Salinas M. Neuropharmacology2017, 125, 429-440.
[117] Sun D.; Yu Y.; Xue X.; Pan M.; Wen M.; Li S.; Qu Q.; Li X.; Zhang L.; Li X.; Liu L.; Yang M.; Tian C. Cell Discov2018, 4, 27.
[118] Salinas M.; Kessler P.; Douguet D.; Sarraf D.; Tonali N.; Thai R.; Servent D.; Lingueglia E. Neuropharmacology2021, 185, 108453.
[119] Blanchard M.G.; Rash L.D.; Kellenberger, S. Br. J. Pharmacol.2012, 165 (7), 2167-2177.
[120] Deval E.; Noël J.; Gasull X.; Delaunay A.; Alloui A.; Friend V.; Eschalier A.; Lazdunski M.; Lingueglia E. J Neurosci2011, 31 (16), 6059-6066.
[121] Peigneur S.; Béress L.; Möller C.; Marí F.; Forssmann W.-G.; Tytgat J. FASEB J2012, 26 (12), 5141-5151.
[122] Rahman T.; Smith, E.S.J. Biochem. Biophys. Res. Commun.2014, 450 (1), 384-389.
[123] Bohlen C.J.; Chesler A.T.; Sharif-Naeini R.; Medzihradszky K.F.; Zhou S.; King D.; Sánchez E.E.; Burlingame A.L.; Basbaum A.I.; Julius D. Nature2011, 479 (7373), 410-414.
[124] Lynagh T.; Romero-Rojo J.L.; Lund C.; Pless, S.A. J. Med. Chem.2017, 60 (19), 8192-8200.
[125] Voilley N.; de Weille J.; Mamet J.; Lazdunski M. J Neurosci2001, 21 (20), 8026-8033.
[126] Lin Y.-W.; Min M.-Y.; Lin C.-C.; Chen W.-N.; Wu W.-L.; Yu H.-M.; Chen C.-C. Neuroscience2008, 151 (2), 544-557.
[127] Osmakov D.I.; Koshelev S.G.; Andreev Y.A.; Kozlov, S.A. Front. Mol. Neurosci.2017, 10, 282.
[128] Zaremba M.; Ruiz-Velasco V. Mol. Pharmacol.2019, 95 (5), 519-527.
[129] Osmakov D.I.; Onoprienko L.V.; Kalinovskii A.P.; Koshelev S.G.; Stepanenko V.N.; Andreev Y.A.; Kozlov S.A.Int. J. Mol. Sci. 2024.
[130] Roush G.C.; Ernst M.E.; Kostis J.B.; Yeasmin S.; Sica D.A. J. Hypertens.2016, 34 (1), 11-19.
[131] Dulai J.S.; Smith E.St.J.; Rahman T. Channels2021, 15 (1), 94-127.
[132] Rivera-de-Torre E.; Rimbault C.; Jenkins T.P.; Sørensen C.V.; Damsbo A.; Saez N.J.; Duhoo Y.; Hackney C.M.; Ellgaard L.; Laustsen, A.H. Front. Bioeng. Biotechnol.2021, 9, 811905.
[133] Stewart E.J.; Aslund F.; Beckwith J. EMBO J1998, 17 (19), 5543-5550.
[134] Salinas G.; Pellizza L.; Margenat M.; Fló M.; Fernández C. Biotechnol. J.2011, 6 (6), 686-699.
[135] Baumgarten T.; Ytterberg A.J.; Zubarev R.A.; de Gier, J.-W. Appl. Environ. Microbiol.2018, 84 (12), e00270-18.
[136] Freudl, R. Microb. Cell Fact. 2018, 17 (1), 52.
[137] Bessette P.H.; Aslund F.; Beckwith J.; Georgiou, G. Proc. Natl. Acad. Sci. U.S.A.1999, 96 (24), 13703-13708.
[138] Ritz D.; Lim J.; Reynolds C.M.; Poole L.B.; Beckwith J. Science2001, 294 (5540), 158-160.
[139] Lobstein J.; Emrich C.A.; Jeans C.; Faulkner M.; Riggs P.; Berkmen, M. Microb. Cell Fact.2012, 11 (1), 753.
[140] Alanen H.I.; Walker K.L.; Lourdes Velez Suberbie M.; Matos C.F.R.O.; Bönisch S.; Freedman R.B.; Keshavarz-Moore E.; Ruddock L.W.; Robinson, C. Biochim. Biophys. Acta2015, 1853 (3), 756-763.
[141] Nguyen V.D.; Hatahet F.; Salo K.E.H.; Enlund E.; Zhang C.; Ruddock, L.W. Microb. Cell Fact.2011, 10, 1.
[142] Bertelsen A.B.; Hackney C.M.; Bayer C.N.; Kjelgaard L.D.; Rennig M.; Christensen B.; Sørensen E.S.; Safavi-Hemami H.; Wulff T.; Ellgaard L.; Nørholm M.H.H. Microb. Biotechnol.2021, 14 (6), 2566-2580.
[143] Schlegel S.; Löfblom J.; Lee C.; Hjelm A.; Klepsch M.; Strous M.; Drew D.; Slotboom D.J.; de Gier, J.-W. J. Mol. Biol.2012, 423 (4), 648-659.
[144] Zhu L.; Yuan C.; Chen Z.; Wang W.; Huang M. Toxicon2010, 55 (2-3), 375-380.
[145] Ahmad M.; Hirz M.; Pichler H.; Schwab, H. Appl. Microbiol. Biotechnol.2014, 98 (12), 5301-5317.
[146] Zhou Q.; Qiu, H. J. Pharm. Sci.2019, 108 (4), 1366-1377.
[147] Karbalaei M.; Rezaee S.A.; Farsiani, H. J. Cell. Physiol.2020, 235 (9), 5867-5881.
[148] Jacobs P.P.; Geysens S.; Vervecken W.; Contreras R.; Callewaert N. Nat. Protoc.2009, 4 (1), 58-70.
[149] O’Flaherty R.; Bergin A.; Flampouri E.; Mota L.M.; Obaidi I.; Quigley A.; Xie Y.; Butler M. Biotechnol. Adv.2020, 43, 107552.
[150] Yadav D.K.; Yadav N.; Yadav S.; Haque S.; Tuteja, N. Arch. Biochem. Biophys.2016, 612, 57-77.
[151] Ki M.-R.; Pack, S.P. Appl. Microbiol. Biotechnol.2020, 104 (6), 2411-2425.
[152] Kapust R.B.; Waugh D.S. Protein Sci.1999, 8 (8), 1668-1674.
[153] Raran-Kurussi S.; Keefe K.; Waugh, D.S. Protein Expression Purif.2015, 110, 159-164.
[154] di Guan C.; Li P.; Riggs P.D.; Inouye H. Gene1988, 67 (1), 21-30.
[155] Kaplan W.; Hüsler P.; Klump H.; Erhardt J.; Sluis-Cremer N.; Dirr H. Protein Sci1997, 6 (2), 399-406.
[156] Lim K.; Ho J.X.; Keeling K.; Gilliland G.L.; Ji X.; Rüker F.; Carter D.C. Protein Sci1994, 3 (12), 2233-2244.
[157] Smith M.; Turki-Judeh W.; Courey A.J. Biomolecules2012, 2 (3), 331-349.
[158] Krumova P.; Meulmeester E.; Garrido M.; Tirard M.; Hsiao H.-H.; Bossis G.; Urlaub H.; Zweckstetter M.; Kügler S.; Melchior F.; Bähr M.; Weishaupt, J.H. J Cell Biol2011, 194 (1), 49-60.
[159] Melchior, F. Annu. Rev. Cell Dev. Biol.2000, 16, 591-626.
[160] Kuo D.; Nie M.; Courey, A.J. Methods Mol Biol2014, 1177, 71-80.
[161] Dashivets T.; Wood N.; Hergersberg C.; Buchner J.; Haslbeck M. Chembiochem2009, 10 (5), 869-876.
[162] Bernier S.C.; Cantin L.; Salesse, C. Protein Expression Purif.2018, 152, 92-106.
[163] Hopp T.P.; Prickett K.S.; Price V.L.; Libby R.T.; March C.J.; Pat Cerretti D.; Urdal D.L.; Conlon P.J. Nat Biotechnol1988, 6 (10), 1204-1210.
[164] Kane, J.F. Curr. Opin. Biotechnol. 1995, 6 (5), 494-500.
[165] Liu B.; Kong Q.; Zhang D.; Yan L. 3 Biotech2018, 8 (4), 210.
[166] Baeshen M.N.; Al-Hejin A.M.; Bora R.S.; Ahmed M.M.M.; Ramadan H.A.I.; Saini K.S.; Baeshen N.A.; Redwan, E.M. J. Microbiol. Biotechnol.2015, 25 (7), 953-962.
[167] Chen P.-Y.; Yi Y.-C.; Wang H.-C.; Ng, I.-S. Appl. Biochem. Biotechnol.2023, 195 (7), 4524-4536.
[168] Tegel H.; Tourle S.; Ottosson J.; Persson, A. Protein Expression Purif.2010, 69 (2), 159-167.
[169] Ouephanit C.; Boonvitthya N.; Bozonnet S.; Chulalaksananukul W. Molecules2019, 24 (19), 3515.
[170] Fahnert B.; Lilie H.; Neubauer, P. Adv Biochem Eng Biotechnol2004, 89, 93-142.
[171] Khattar S.K.; Gulati P.; Kundu P.K.; Singh V.; Bughani U.; Bajpai M.; Saini, K.S. Protein Pept. Lett.2007, 14 (8), 756-760.
[172] Ma, Y.; Lee, C.-J.; Park, J.-S. Antibiotics (Basel, Switz.) 2020, 9 (9), 541.
[173] Yang Q.; Xu J.; Li M.; Lei X.; An L. Biotechnol. Lett2003, 25 (8), 607-610.
[174] Lawrence P.B.; Price, J.L. Curr. Opin. Chem. Biol.2016, 34, 88-94.
[175] Norton, R.S. Expert Opin. Drug Discovery2017, 12 (6), 611-623.
[176] Pinheiro-Junior E.L.; Boldrini-França J.; Takeda A.A.S.; Costa T.R.; Peigneur S.; Cardoso I.A.; Oliveira, I.S. de; Sampaio, S.V.; de Mattos Fontes M.R.; Tytgat J.; Arantes, E.C. Int. J. Biol. Macromol.2021, 190, 564-573.
[177] Tanner M.R.; Tajhya R.B.; Huq R.; Gehrmann E.J.; Rodarte K.E.; Atik M.A.; Norton R.S.; Pennington M.W.; Beeton C. Clin Immunol2017, 180, 45-57.
[178] Wender P.A.; Mitchell D.J.; Pattabiraman K.; Pelkey E.T.; Steinman L.; Rothbard, J.B. Proc. Natl. Acad. Sci.2000, 97 (24), 13003-13008.
[179] Teesalu T.; Sugahara K.N.; Kotamraju V.R.; Ruoslahti, E. Proc. Natl. Acad. Sci. U.S.A.2009, 106 (38), 16157-16162.
[180] Otvos L.; Wade J.D. Front. Chem.2014, 2, 62.
[181] Egleton R.D.; Davis T.P. NeuroRx2005, 2 (1), 44-53.
[182] Egleton R.D.; Mitchell S.A.; Huber J.D.; Palian M.M.; Polt R.; Davis, T.P. J Pharmacol Exp Ther2001, 299 (3), 967-972.
[183] Desino K.E.; Pignatello R.; Guccione S.; Basile L.; Ansar S.; Michaelis M.L.; Ramsay R.R.; Audus K.L. Biochem. Pharmacol.2009, 78 (11), 1412-1417.
[184] Pignatello R.; Puleo A.; Guccione S.; Raciti G.; Acquaviva R.; Campisi A.; Ventura C.A.; Puglisi, G. Eur. J. Med. Chem.2005, 40 (11), 1074-1079.
[185] Wang J.; Hogenkamp D.J.; Tran M.; Li W.-Y.; Yoshimura R.F.; Johnstone T.B.C.; Shen W.-C.; Gee, K.W. J. Drug Targeting2006, 14 (3), 127-136.
[186] Varamini P.; Toth I. Front. Pharmacol.2013, 4, 155.
[187] Tripathi A.; Varadarajan, R. Curr. Opin. Struct. Biol.2014, 24, 63-71.
[188] Crameri A.; Raillard S.A.; Bermudez E.; Stemmer W.P. Nature1998, 391 (6664), 288-291.
[189] Shcherbatko A.; Rossi A.; Foletti D.; Zhu G.; Bogin O.; Galindo Casas M.; Rickert M.; Hasa-Moreno A.; Bartsevich V.; Crameri A.; Steiner A.R.; Henningsen R.; Gill A.; Pons J.; Shelton D.L.; Rajpal A.; Strop, P. J Biol Chem2016, 291 (27), 13974-13986.
[190] Muntoni E.; Marini E.; Ahmadi N.; Milla P.; Ghè C.; Bargoni A.; Capucchio M.T.; Biasibetti E.; Battaglia L. Acta Diabetol.2019, 56 (12), 1283-1292.
[191] Griesser J.; Hetényi G.; Moser M.; Demarne F.; Jannin V.; Bernkop-Schnürch, A. Int. J. Pharm.2017, 520 (1-2), 267-274.
[192] Fonte P.; Araújo F.; Reis S.; Sarmento, B. J. Diabetes Sci. Technol.2013, 7 (2), 520-531.
[193] Haddadzadegan S.; Dorkoosh F.; Bernkop-Schnürch, A. Adv. Drug Delivery Rev.2022, 182, 114097.
[194] Hintzen F.; Perera G.; Hauptstein S.; Müller C.; Laffleur F.; Bernkop-Schnürch, A. Int. J. Pharm.2014, 472 (1-2), 20-26.
[195] Scannell J.W.; Blanckley A.; Boldon H.; Warrington, B. Nat. Rev. Drug Discov.2012, 11 (3), 191-200.
[196] Xu Y.-Y.; Ma X.-H.; Zhang, S.-J. Int. J. Clin. Pharm. Th.2016, 54 (2), 129-134.
[197] Wei J.; Zhu M.; Zhang Z.; Jia Z.; He X.; Wan Y.; Wang S.; Xiu D.; Tang Y.; Li J.; Xu J.; Heng, Q. Chinese Med. J-peking.2010, 123 (5), 589-593.
[198] Markland, F.S.; Swenson, S. Toxins (Basel) 2010, 2 (4), 793-808.
[199] Shah A.R.; Scher L. IDrugs2007, 10 (5), 329-335.
[200] Iannone, L.F.; Nassini, R.; Patacchini, R.; Geppetti, P.; De Logu, F. Temperature (Austin) 2023, 10 (1), 50-66.
[201] Dong C.-R.; Zhang W.-J.; Luo H.-L. Biomed Pharmacother2022, 150, 113029.
Outlines

/