Abstract
Background: Iron chelators (ICs) have recently emerged as one of the new
methods of treatment for viral infections. This study aimed to evaluate the efficiency
and safety of natural ICs compared to synthetic ICs. Natural and synthetic ICs are the
most common therapeutic agents tested for the treatment of viral infections. When evaluated
against synthetic ICs, natural ICs are probably favored owing to their lower toxicity
and safer properties. The main objective of the present systematic review was to assess
the current evidence on the role of pharmacological mechanisms in the treatment of viral
infections.
Methods: This study was designed as a systematic review in which search strategies
were focused on two electronic databases, PubMed, and Scopus, between 2017 and
2021. A search filter with two subjects, “iron chelators” and “viral infection”, was employed.
Results: According to the results, both natural and synthetic chelators had a considerable
impact on the treatment of viral infections
via various mechanisms, with natural
ICs being the most extensively used.
Conclusion: Natural and synthetic ICs exert their effects through different pharmacological
mechanisms. Among these compounds, natural chelators are more widely used due
to their safety, efficacy, and a wider range of applications.
Mirza A.Z.; Shamshad H.; Osra F.A.; Habeebullah T.M.; Morad M.; An overview of viruses discovered over the last decades and drug development for the current pandemic. Eur J Pharmacol 2021,890,173746
10.1016/j.ejphar.2020.173746
33221318
Wu F.; Zhao S.; Yu B.; Chen Y.M.; Wang W.; Song Z.G.; Hu Y.; Tao Z.W.; Tian J.H.; Pei Y.Y.; Yuan M.L.; Zhang Y.L.; Dai F.H.; Liu Y.; Wang Q.M.; Zheng J.J.; Xu L.; Holmes E.C.; Zhang Y.Z.; A new coronavirus associated with human respiratory disease in China. Nature 2020,579(7798),265-269
10.1038/s41586-020-2008-3
32015508
WHO estimated that in 2019, approximately 290, 000 people died from hepatitis C 2019. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-c#:~:text=WHO%20estimated%20that%20in%202019%2C%20approximately%20290%20000,is%20currently%20no%20effective%20vaccine%20against%20hepatitis%20C2019
In 2019, hepatitis B resulted in an estimated 820, 000 deaths. Available from: https://www.who.int/news-room/fact-sheets/detail/hepatitis-b2019
Schmidt S.M.; The role of iron in viral infections. Front Biosci 2020,25(4),893-911
10.2741/4839
31585922
Aslam N.; Sarfaraz I.M.; Makhdoom H.S.; Rizwan M.; Naseer Q.U.A.; Afzal M.; Muneer R.; Batool F.; Effects of chelating agents on heavy metals in Hepatitis C Virus (HCV) patients. Math Biosci Eng 2019,16(3),1138-1149
10.3934/mbe.2019054
30947412
Meyer D.; Iron chelation as therapy for HIV and Mycobacterium tuberculosis co-infection under conditions of iron overload. Curr Pharm Des 2006,12(16),1943-1947
10.2174/138161206777442164
16787239
Hatcher H.C.; Singh R.N.; Torti F.M.; Torti S.V.; Synthetic and natural iron chelators: Therapeutic potential and clinical use. Future Med Chem 2009,1(9),1643-1670
10.4155/fmc.09.121
21425984
Buss J.; Torti F.; Torti S.; The role of iron chelation in cancer therapy. Curr Med Chem 2003,10(12),1021-1034
10.2174/0929867033457638
12678674
Dalamaga M.; Karampela I.; Mantzoros C.S.; Commentary: Could iron chelators prove to be useful as an adjunct to COVID-19 treatment regimens? Metabolism 2020,108,154260
10.1016/j.metabol.2020.154260
32418885
Williams A.; Meyer D.; Desferrioxamine as immunomodulatory agent during microorganism infection. Curr Pharm Des 2009,15(11),1261-1268
10.2174/138161209787846801
19355965
Liu W.; Zhang S.; Nekhai S.; Liu S.; Depriving iron supply to the virus represents a promising adjuvant therapeutic against viral survival. Curr Clin Microbiol Rep 2020,7(2),13-19
10.1007/s40588-020-00140-w
32318324
Saxena D.; Spino M.; Tricta F.; Connelly J.; Cracchiolo B.M.; Hanauske A.R.; D’Alliessi G.D.; Mathews M.B.; Karn J.; Holland B.; Park M.H.; Pe’ery T.; Palumbo P.E.; Hanauske-Abel H.M.; Drug-based lead discovery: the novel ablative antiretroviral profile of deferiprone in HIV-1-infected cells and in HIV-infected treatment-naive subjects of a double-blind, placebo-controlled, randomized exploratory trial. PLoS One 2016,11(5),e0154842
10.1371/journal.pone.0154842
27191165
Habib H.M.; Ibrahim S.; Zaim A.; Ibrahim W.H.; The role of iron in the pathogenesis of COVID-19 and possible treatment with lactoferrin and other iron chelators. Biomed Pharmacother 2021,136,111228
10.1016/j.biopha.2021.111228
33454595
Khan N.; Chen X.; Geiger J.D.; Role of divalent cations in HIV-1 replication and pathogenicity. Viruses 2020,12(4),471
10.3390/v12040471
32326317
Farkas E.; Enyedy É.A.; Zékány L.; Deák G.; Interaction between iron(II) and hydroxamic acids: Oxidation of iron(II) to iron(III) by desferrioxamine B under anaerobic conditions. J Inorg Biochem 2001,83(2-3),107-114
10.1016/S0162-0134(00)00197-5
11237249
Shankaran P.; Madlenakova M.; Hajkova V.; Jilich D.; Svobodova I.; Horinek A.; Fujikura Y.; Melkova Z.; Effects of heme degradation products on reactivation of latent HIV-1. Acta Virol 2017,61(1),86-96
10.4149/av_2017_01_86
28161963
Muhoberac B.B.; What can cellular redox, iron, and reactive oxygen species suggest about the mechanisms and potential therapy of COVID-19? Front Cell Infect Microbiol 2020,10,569709
10.3389/fcimb.2020.569709
33381464
Abobaker A.; Can iron chelation as an adjunct treatment of COVID-19 improve the clinical outcome? Eur J Clin Pharmacol 2020,76(11),1619-1620
10.1007/s00228-020-02942-9
32607779
Abobaker A.; Reply: Iron chelation may harm patients with COVID-19. Eur J Clin Pharmacol 2021,77(2),267-268
10.1007/s00228-020-02988-9
32870381
Zou D.M.; Rong D.D.; Zhao H.; Su L.; Sun W.L.; Improvement of chronic hepatitis B by iron chelation therapy in a patient with iron overload. Medicine 2017,96(52),e9566
10.1097/MD.0000000000009566
29384977
Masson P.L.; Heremans J.F.; Lactoferrin in milk from different species. Comp Biochem Physiol B 1971,39(1),119-IN13
10.1016/0305-0491(71)90258-6
4998849
Campione E.; Lanna C.; Cosio T.; Rosa L.; Conte M.P.; Iacovelli F.; Romeo A.; Falconi M.; Del Vecchio C.; Franchin E.; Lia M.S.; Minieri M.; Chiaramonte C.; Ciotti M.; Nuccetelli M.; Terrinoni A.; Iannuzzi I.; Coppeda L.; Magrini A.; Bernardini S.; Sabatini S.; Rosapepe F.; Bartoletti P.L.; Moricca N.; Di Lorenzo A.; Andreoni M.; Sarmati L.; Miani A.; Piscitelli P.; Valenti P.; Bianchi L.; Lactoferrin against SARS-CoV-2: In vitro and in silico evidence. Front Pharmacol 2021,12,666600
10.3389/fphar.2021.666600
34220505
Scott L.E.; Orvig C.; Medicinal inorganic chemistry approaches to passivation and removal of aberrant metal ions in disease. Chem Rev 2009,109(10),4885-4910
10.1021/cr9000176
19637926
Khodaverdian V.; Tapadar S.; MacDonald I.A.; Xu Y.; Ho P.Y.; Bridges A.; Rajpurohit P.; Sanghani B.A.; Fan Y.; Thangaraju M.; Hathaway N.A.; Oyelere A.K.; Deferiprone: Pan-selective histone lysine demethylase inhibition activity and structure- activity relationship study. Sci Rep 2019,9(1),4802
10.1038/s41598-019-39214-1
30886160
Suwanprinya L.; Morales N.P.; Sanvarinda P.; Dieng H.; Okabayashi T.; Morales Vargas R.E.; Dengue virus-induced reactive oxygen species production in rat microglial cells. Jpn J Infect Dis 2017,70(4),383-387
10.7883/yoken.JJID.2016.236
28003593
Joseph M.; Sreekanth A.; Suni V.; Kurup M.R.P.; Spectral characterization of iron(III) complexes of 2-benzoylpyridine N(4)-substituted thiosemicarbazones. Spectrochim Acta A Mol Biomol Spectrosc 2006,64(3),637-641
10.1016/j.saa.2005.07.067
16386946
Buesa J.; Grand challenge in viral disease investigation: An endless endeavor. Front Virol 2021,1,692105
10.3389/fviro.2021.692105
Allahverdipour H.; Global challenge of health communication: Infodemia in the coronavirus disease (COVID-19) pandemic. J Educ Community Health 2020,7(2),65-67
10.29252/jech.7.2.65
Chhabra R.; Saha A.; Chamani A.; Schneider N.; Shah R.; Nanjundan M.; Iron pathways and iron chelation approaches in viral, microbial, and fungal infections. Pharmaceuticals 2020,13(10),275
10.3390/ph13100275
32992923
Liu J.R.; Liu Y.; Yin F.Z.; Liu B.W.; Serum ferritin, an early marker of cardiovascular risk: a study in Chinese men of first-degree relatives with family history of type 2 diabetes. BMC Cardiovasc Disord 2019,19(1),82
10.1186/s12872-019-1068-5
30943893
Duchemin J.B.; Paradkar P.N.; Iron availability affects West Nile virus infection in its mosquito vector. Virol J 2017,14(1),103
10.1186/s12985-017-0770-0
28583206
Perricone C.; Bartoloni E.; Bursi R.; Cafaro G.; Guidelli G.M.; Shoenfeld Y.; Gerli R.; COVID-19 as part of the hyperferritinemic syndromes: The role of iron depletion therapy. Immunol Res 2020,68(4),213-224
10.1007/s12026-020-09145-5
32681497
van Asbeck B.S.; Georgiou N.A.; van der Bruggen T.; Oudshoorn M.; Nottet H.S.L.M.; Marx J.J.M.; Anti-HIV effect of iron chelators: Different mechanisms involved. J Clin Virol 2001,20(3),141-147
10.1016/S1386-6532(00)00122-0
11166663
Debebe Z.; Ammosova T.; Jerebtsova M.; Kurantsin-Mills J.; Niu X.; Charles S.; Richardson D.R.; Ray P.E.; Gordeuk V.R.; Nekhai S.; Iron chelators ICL670 and 311 inhibit HIV-1 transcription. Virology 2007,367(2),324-333
10.1016/j.virol.2007.06.011
17631934
Ricchi P.; Cinque P.; Lanza Galeota A.; Di Matola T.; Ammirabile M.; Prossomariti L.; Hepatitis B virus reactivation during combined therapy with deferiprone and desferioxamine in a hepatitis B surface antigen thalassemic carrier. Int J Hematol 2009,89(2),135-138
10.1007/s12185-008-0229-6
19107332
Flora S.J.S.; Pachauri V.; Chelation in metal intoxication. Int J Environ Res Public Health 2010,7(7),2745-2788
10.3390/ijerph7072745
20717537
Mancinelli R.; Rosa L.; Cutone A.; Lepanto M.S.; Franchitto A.; Onori P.; Gaudio E.; Valenti P.; Viral hepatitis and iron dysregulation: Molecular pathways and the role of lactoferrin. Molecules 2020,25(8),1997
10.3390/molecules25081997
32344579
Singh A.; Ahmad N.; Varadarajan A.; Vikram N.; Singh T.P.; Sharma S.; Sharma P.; Lactoferrin, a potential iron-chelator as an adjunct treatment for mucormycosis – A comprehensive review. Int J Biol Macromol 2021,187,988-998
10.1016/j.ijbiomac.2021.07.156
34324905
Arandi N.; Haghpanah S.; Safaei S.; Zahedi Z.; Ashrafi A.; Eatemadfar P.; Zarei T.; Radwan A.H.; Taher A.T.; Karimi M.; Combination therapy – deferasirox and deferoxamine – in thalassemia major patients in emerging countries with limited resources. Transfus Med 2015,25(1),8-12
10.1111/tme.12188
25801075
Voskaridou E.; Komninaka V.; Karavas A.; Terpos E.; Akianidis V.; Christoulas D.; Combination therapy of deferasirox and deferoxamine shows significant improvements in markers of iron overload in a patient with β-thalassemia major and severe iron burden. Transfusion 2014,54(3),646-649
10.1111/trf.12335
23834310
Sane A.; Manzi S.; Perfect J.; Herzberg A.J.; Moore J.O.; Deferoxamine treatment as a risk factor for zygomycete infection. J Infect Dis 1989,159(1),151-152
10.1093/infdis/159.1.151
2909637
Kontoghiorghes G.J.; New concepts of iron and aluminium chelation therapy with oral L1 (deferiprone) and other chelators. A review. Analyst 1995,120(3),845-851
10.1039/an9952000845
7741239
Addis A.; Loebstein R.; Koren G.; Einarson T.R.; Meta-analytic review of the clinical effectiveness of oral deferiprone (L 1 ). Eur J Clin Pharmacol 1999,55(1),1-6
10.1007/s002280050584
10206077
Chen X.; Yu C.; Kang R.; Tang D.; Iron metabolism in ferroptosis. Front Cell Dev Biol 2020,8,590226
10.3389/fcell.2020.590226
33117818
Dixon SJ; Lemberg KM; Lamprecht MR; Skouta R; Zaitsev EM; Gleason CE; Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell 2012,149(5),1060-1072
Yao X.; Zhang Y.; Fan B-Y.; Pang Y-L.; Shen W-Y.; Wang X.; Zhao C-X.; Li W-X.; Liu C.; Kong X-H.; Ning G-Z.; Feng S-Q.; Neuroprotective effect of deferoxamine on erastininduced ferroptosis in primary cortical neurons. Neural Regen Res 2020,15(8),1539-1545
10.4103/1673-5374.274344
31997820
Grignano E.; Birsen R.; Chapuis N.; Bouscary D.; From iron chelation to overload as a therapeutic strategy to induce ferroptosis in leukemic cells. Front Oncol 2020,10,586530
10.3389/fonc.2020.586530
33042852
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