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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Triple Action of Lignosulfonic Acid Sodium: Anti-protease, Antioxidant, and Anti-inflammatory Effects of a Polymeric Heparin Mimetic

Author(s): Rami A. Al-Horani* and Kholoud F. Aliter

Volume 20, Issue 4, 2024

Published on: 08 January, 2024

Page: [414 - 421] Pages: 8

DOI: 10.2174/0115734064275120231222111145

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Abstract

Background: Heparins are sulfated glycosaminoglycans that are used as anticoagulants to treat thrombosis. Heparins exhibit other potential therapeutic effects, such as anti-inflammatory, anti-viral, and anti-malarial effects. However, the strong anticoagulant activity of heparins poses a risk of life-threatening bleeding, limiting their therapeutic use for other diseases beyond thrombosis. To exploit the other effects of heparins and eliminate the bleeding risk, we explored an alternative polymer called lignosulfonic acid sodium (LSAS), which acts as a sulfonated heparin mimetic. LSAS targets factor XIa to exert an anticoagulant effect, and thus, unlike heparins, it is unlikely to cause bleeding.

Methods: This study investigated the multiple effects of LSAS to identify potential leads for complex pathologies treatment. A series of chromogenic substrate hydrolysis assays were used to evaluate the inhibition of three inflammation-related proteases by LSAS. Its chemical antioxidant activity against the system of ABTS/hydrogen peroxide/metmyoglobin was also determined. Lastly, the effect of LSAS on TNFα-induced activation of the NF-κB pathway in HEK-293 cells was also tested to determine its cellular anti-inflammatory activity.

Results: The results showed that LSAS effectively inhibited human neutrophil elastase, cathepsin G, and plasmin, with IC50 values ranging from 0.73 to 212.5 μg/mL. Additionally, LSAS demonstrated a significant chemical antioxidant effect, with an IC50 value of 44.1 μg/mL. Furthermore, at a concentration of approximately 530 μg/mL, LSAS inhibited the TNFα-induced activation of the NF-κB pathway in HEK-293 cells, indicating a substantial anti-inflammatory effect. An essential advantage of LSAS is its high water solubility and virtual non-toxicity, making it a safe and readily available polymer.

Conclusion: Based on these findings, LSAS is put forward as a polymeric heparin mimetic with multiple functions, serving as a potential platform for developing novel therapeutics to treat complex pathologies.

Keywords: LSAS, lignosulfonic acid, heparin mimetic, neutrophil elastase, cathepsin G, plasmin, anti-protease, anti-oxidative, anti-inflammatory.

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[1]
Kar, S.; Bankston, P.; Afosah, D.K.; Al-Horani, R.A. Lignosulfonic acid sodium is a noncompetitive inhibitor of human factor XIa. Pharmaceuticals, 2021, 14(9), 886.
[http://dx.doi.org/10.3390/ph14090886] [PMID: 34577586]
[2]
Qiu, M.; Wang, Q.; Chu, Y.; Yuan, Z.; Song, H.; Chen, Z.; Wu, Z. Lignosulfonic acid exhibits broadly anti-HIV-1 activity-potential as a microbicide candidate for the prevention of HIV-1 sexual transmission. PLoS One, 2012, 7(4), e35906.
[http://dx.doi.org/10.1371/journal.pone.0035906] [PMID: 22558266]
[3]
Tollner, T.L.; Overstreet, J.W.; Li, M.W.; Meyers, S.A.; Yudin, A.I.; Salinas, E.R.; Cherr, G.N. Lignosulfonic acid blocks in vitro fertilization of macaque oocytes when sperm are treated either before or after capacitation. J. Androl., 2002, 23(6), 889-898.
[PMID: 12399536]
[4]
Suzuki, H.; Tochikura, T.S.; Iiyama, K.; Yamazaki, S.; Yamamoto, N.; Toda, S. Lignosulfonate, a water-solubilized lignin from the waste liquor of the pulping process, inhibits the infectivity and cytopathic effects of human immunodeficiency virus in vitro. Agric. Biol. Chem., 1989, 53(12), 3369-3372.
[5]
Saluja, B.; Thakkar, J.N.; Li, H.; Desai, U.R.; Sakagami, M. Novel low molecular weight lignins as potential anti-emphysema agents: In vitro triple inhibitory activity against elastase, oxidation and inflammation. Pulm. Pharmacol. Ther., 2013, 26(2), 296-304.
[http://dx.doi.org/10.1016/j.pupt.2012.12.009] [PMID: 23280431]
[6]
Chiang, C.C.; Korinek, M.; Cheng, W.J.; Hwang, T.L. Targeting neutrophils to treat acute respiratory distress syndrome in coronavirus disease. Front. Pharmacol., 2020, 11, 572009.
[http://dx.doi.org/10.3389/fphar.2020.572009] [PMID: 33162887]
[7]
Al-Horani, R.A.; Afosah, D.K.; Kar, S.; Aliter, K.F.; Mottamal, M. Sulphated penta-galloyl glucopyranoside (SPGG) is glycosaminoglycan mimetic allosteric inhibitor of cathepsin G. RPS Pharm. Pharmacol. Rep., 2023, 2(1), 001.
[http://dx.doi.org/10.1093/rpsppr/rqad001]
[8]
Al-Horani, R.A.; Desai, U.R. Recent advances on plasmin inhibitors for the treatment of fibrinolysis-related disorders. Med. Res. Rev., 2014, 34(6), 1168-1216.
[http://dx.doi.org/10.1002/med.21315] [PMID: 24659483]
[9]
Afosah, D.K.; Al-Horani, R.A.; Sankaranarayanan, N.V.; Desai, U.R. Potent, selective, allosteric inhibition of human plasmin by sulfated non-saccharide glycosaminoglycan mimetics. J. Med. Chem., 2017, 60(2), 641-657.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01474] [PMID: 27976897]
[10]
Loomis, T.A.; Beyer, R.E. Heparin-like anticoagulant action of sulfonated lignins from commercial waste sulfite liquor. J. Pharmacol. Exp. Ther., 1953, 109(1), 21-25.
[PMID: 13097330]
[11]
Al-Horani, R.A.; Aliter, K.F.; Kar, S.; Mottamal, M. Sulfonated nonsaccharide heparin mimetics are potent and noncompetitive inhibitors of human neutrophil elastase. ACS Omega, 2021, 6(19), 12699-12710.
[http://dx.doi.org/10.1021/acsomega.1c00935] [PMID: 34056422]
[12]
Conner, E.M.; Grisham, M.B. Inflammation, free radicals, and antioxidants. Nutrition, 1996, 12(4), 274-277.
[http://dx.doi.org/10.1016/S0899-9007(96)00000-8] [PMID: 8862535]
[13]
Lingappan, K. NF-κB in oxidative stress. Curr. Opin. Toxicol., 2018, 7, 81-86.
[http://dx.doi.org/10.1016/j.cotox.2017.11.002] [PMID: 29862377]
[14]
Nenadis, N.; Lazaridou, O.; Tsimidou, M.Z. Use of reference compounds in antioxidant activity assessment. J. Agric. Food Chem., 2007, 55(14), 5452-5460.
[http://dx.doi.org/10.1021/jf070473q] [PMID: 17579432]
[15]
Gülçin, I. Antioxidant activity of caffeic acid (3,4-dihydroxycinnamic acid). Toxicology, 2006, 217(2-3), 213-220.
[http://dx.doi.org/10.1016/j.tox.2005.09.011] [PMID: 16243424]
[16]
Rice-Evans, C.A.; Miller, N.J.; Paganga, G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med., 1996, 20(7), 933-956.
[http://dx.doi.org/10.1016/0891-5849(95)02227-9] [PMID: 8743980]
[17]
Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-κB signaling in inflammation. Signal Transduct. Target. Ther., 2017, 2(1), 17023.
[http://dx.doi.org/10.1038/sigtrans.2017.23] [PMID: 29158945]
[18]
Vinardell, M.; Mitjans, M. Lignins and their derivatives with beneficial effects on human health. Int. J. Mol. Sci., 2017, 18(6), 1219.
[http://dx.doi.org/10.3390/ijms18061219] [PMID: 28590454]
[19]
Al-Horani, R.A.; Gailani, D.; Desai, U.R. Allosteric inhibition of factor XIa. Sulfated non-saccharide glycosaminoglycan mimetics as promising anticoagulants. Thromb. Res., 2015, 136(2), 379-387.
[http://dx.doi.org/10.1016/j.thromres.2015.04.017] [PMID: 25935648]
[20]
Al-Horani, R.A.; Afosah, D.K. Recent advances in the discovery and development of factor XI/XIa inhibitors. Med. Res. Rev., 2018, 38(6), 1974-2023.
[http://dx.doi.org/10.1002/med.21503] [PMID: 29727017]
[21]
Hogwood, J.; Mulloy, B.; Lever, R.; Gray, E.; Page, C.P. Pharmacology of heparin and related drugs: An update. Pharmacol. Rev., 2023, 75(2), 328-379.
[http://dx.doi.org/10.1124/pharmrev.122.000684] [PMID: 36792365]
[22]
Environmental Protection Agency 2005. Available from: https://www.federalregister.gov/documents/2005/02/16/05-2986/lignosulfonates-exemptions-from-the-requirement-of-a-tolerance
[23]
Nahain, A.A.; Ignjatovic, V.; Monagle, P.; Tsanaktsidis, J.; Ferro, V. Heparin mimetics with anticoagulant activity. Med. Res. Rev., 2018, 38(5), 1582-1613.
[http://dx.doi.org/10.1002/med.21489] [PMID: 29446104]

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