Targeting Polyamine Metabolism for Control of Human Viral Diseases

Figures & data

Figure 1 The metabolic pathways of biogenic polyamines.

Table 1 Role of Polyamines in Viral Infection

Virus	Transmission	Host Factor/Pathway	Reagent(s)	Target	Effects/Processes	Viral Level*	P-value	Reference
Coxsackievirus B3	Fecal–oral, placenta	Polyamines	DFMO	ODC1	Prevent the virus from binding to susceptible cells	6.3-fold reduction	<0.01	[^Citation14]
		Polyamines	DFMO	ODC1	Restricted virus replication by quelling viral protease activity	2.8-fold reduction	<0.01	[^Citation15]
		Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	10-fold reduction	<0.05	[^Citation16]
Zika Virus	Mosquito, sex, placenta	Polyamines	DSS-BEN, DSS-PG	SAT1, SMOX	Decreased polyamine availability for viral replication and translation	4-log reduction	<0.001	[^Citation21]
		Polyamines	IFNI	SAT1	Restricted infectious virus replication	2-log reduction	<0.001	[^Citation20]
		Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	15-fold reduction	<0.001	[^Citation16]
Ebola virus	Direct contact	Polyamines, eIF5A	DFMO, GC7, CPX	ODC1, DHPS	Blocked the accumulation of viral mRNA as well as translation	85% decrease	<0.01	[^Citation35]
		Polyamines, eIF5A	DFMO, MDL, SAM486A, GC7,CPX,DEF	ODC1,PAOX SAMDC, DHPS, DOHH	Inhibited infectious virus replication through decreased accumulation of VP30	3-log reduction	<0.0001	[^Citation34]
Marburgvirus	Bodily fluid	Polyamines, eIF5A	CPX	DOHH	Reduced infectious virus replication	3-log reduction	–	[^Citation34]
Chikung unya virus	Mosquito	Polyamines	aaNAT5b	SAT1	Depleted polyamines and limit virus replication	–	–	[^Citation38]
		Polyamines	nsP1-mutants	–	Enhanced virus replication in polyamine depletion	–	–	[^Citation39]
		Polyamines	IFNI	SAT1	Restricted infectious virus replication	3-log reduction	<0.01	[^Citation20]
		Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	200-fold reduction	<0.01	[^Citation16]
Hepatitis C virus	Blood	Polyamines	–	–	Activated virus RNA-dependent RNA polymerase and inhibited virus helicase	7-fold increase	–	[^Citation25]
		Polyamines	–	ODC1, SAT1, SMOX	HCV replicon decreased levels polyamines	–	–	[^Citation26]
		Polyamines	DFMO, DENSpm, MDL72527	ODC1, SAT1, PAOX	Affected cytokine production and inhibit the expression of viral proteins	28–32% decrease	<0.05	[^Citation27]
Hepatitis B virus	Blood, vertical	Polyamines	DMFO	ODC1	Decreased viral replication and levels of protein and capsids	34% and 84% reduction	-	[^Citation29]
Epstein–Barr virus	Oral	Polyamines	DENSpm	SAT1	Increased SAT1 mRNA levels	2.7-fold reduction	-	[^Citation46]
Sindbis virus	Mosquito	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	10-fold reduction	<0.001	[^Citation16]
MERS coronavirus	Spray, contact	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	30-fold reduction	<0.001	[^Citation16]
Dengue virus	Mosquito	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	60-fold reduction	<0.001	[^Citation16]
			RBM10	SAT1	Decreased SAT1 degradation and reduced polyamine levels and restrain virus replication	4.5-fold reduction	<0.001	[^Citation31]
Japanese encephalitis virus	Mosquito	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	5-fold reduction	<0.01	[^Citation16]
Yellow fever virus	Mosquito	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	90-fold reduction	<0.05	[^Citation16]
Enterovirus 71	Fecal–oral, spray	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	12-fold reduction	<0.05	[^Citation16]
Poliovirus	Fecal–oral	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	20-fold reduction	<0.05	[^Citation16]
Rift Valley fever virus	Mosquito, blood	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	200-fold reduction	<0.001	[^Citation16]
		Polyamines	DFMO DENSpm	ODC1, SAT1	Produced excess non-infectious particles and restrict virus infection	100-fold reduction	<0.001	[^Citation58]
		Polyamines	DFMO	ODC1	Produced non-infectious particles and interfere with virus replication	2-log reduction	<0.001	[^Citation59]
Vesicular stomatitis virus	Wound, oral	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	20-fold reduction	<0.01	[^Citation16]
Rabies virus	Bite	Polyamines	DFMO DENSpm	ODC1, SAT1	Reduced infectious virus production	2-fold reduction	<0.001	[^Citation16]
La Crosse virus	Mosquito	Polyamines	DFMO DENSpm	ODC1, SAT1	Produced excess non-infectious particles and restrict virus infection	100-fold reduction	<0.001	[^Citation58]
Human immunodeficiency virus	Sex, blood, placenta	eIF5A	eIF5A siRNA	-	Decreased virus production by inhibiting RNA translation and Rev-induced gene expression	2-fold reduction	<0.01	[^Citation63]
		eIF5A	CPX, DEF	DOHH	Inhibited the expression of HIV-1 promoter at transcription initiation	3-fold reduction	–	[^Citation62]
		eIF5A	eIF5A mutants	Rev complex	Blocked HIV-1 Rev trans-activation and Rev- mediated nuclear export	–	–	[^Citation61]
Herpes simplex virus	Spray, contact	Polyamines	MGBG	SAMDC	Inhibited virus infection	63-fold reduction	–	[^Citation50]
		Polyamines	DFMO	ODC1	Decreased viral infectivity through impairment of DNA synthesis	2-log reduction	–	[^Citation49]
		Polyamines	–	–	Presented in virion to neutralize viral DNA	–	–	[^Citation48]
Human cytomegalovirus	Contact, sex	Polyamines	DFMO	ODC1	Reduced infectious virus production through interfering with virus assembly	6-log reduction	–	[^Citation53]
		Polyamines	DFMO, MGBG	ODC1, SAMDC	Reduced infectious virus	4-log reduction	–	[^Citation52]
Semliki Forest virus	Mosquito	Polyamines	DFMO	ODC1, SAMDC	Inhibited virus production by Interfering with viral protein synthesis	10-fold, 5.6-fold decrease	–	[^Citation42,Citation43]

Note: *Viral level represents experimental time point/condition where the peak effect was observed.

Abbreviations: DFMO, difluoromethornithine; DENSpm, N1,N11-diethylnorspermine; DSS-BEN, BENSpm-based biodegradable polymeric prodrug; DSS-PG, PG11047-based biodegradable polymeric prodrug; GC7, N1-guanyl-1,7-diamineheptane; CPX, ciclopirox; MDL, N,N1-bis(2,3-butadienyl)-1,4-butanediamine; SAM486A, 4-amidinoindan-1-one-2ʹ-amidinhydrazone; DEF, deferiprone; aaNAT5b, a recombinant protein in insects; nsP1, non-structural protein 1; MGBG, methylglyoxal bis(guanylhydrazone); ODC1, ornithine decarboxylase 1; SAT1, spermidine/spermine acetyltransferase; SMOX, spermine oxidase; PAOX, polyamine oxidase; DHPS, deoxyhypusine synthase; SAMDC, S-adenosylmethionine decarboxylase; DOHH, deoxyhypusine hydroxylase.

Kicmal TM, Tate PM, Dial CN, et al. Polyamine depletion abrogates enterovirus cellular attachment. J Virol. 2019;1–37.

 Web of Science ®Google Scholar

Dial CN, Tate PM, Kicmal TM, Mounce BC. Coxsackievirus B3 responds to polyamine depletion via enhancement of 2A and 3C protease activity. Viruses. 2019;11(403):1–15. doi:10.3390/v11050403

 Web of Science ®Google Scholar

Mounce BC, Cesaro T, Moratorio G, et al. Inhibition of polyamine biosynthesis is a broad-spectrum strategy against RNA viruses. J Virol. 2016;90(21):9683–9692. doi:10.1128/JVI.01347-1627535047

 PubMed Web of Science ®Google Scholar

Routhu NK, Xie Y, Dunworth M, et al. Polymeric prodrugs targeting polyamine metabolism inhibit zika virus replication. Mol Pharm. 2018;1–45.

 Google Scholar

Mounce BC, Poirier EZ, Passoni G, et al. Interferon-induced spermidine-spermine acetyltransferase and polyamine depletion restrict zika and chikungunya viruses. Cell Host Microbe. 2016;20(2):167–177. doi:10.1016/j.chom.2016.06.01127427208

 PubMed Web of Science ®Google Scholar

Olsen ME, Cressey TN, Muhlberger E, Connor JH. Differential mechanisms for the involvement of polyamines and hypusinated eif5a in ebola virus gene expression. J Virol. 2018;1–34.

 Web of Science ®Google Scholar

Olsen ME, Filone CM, Rozelle D, et al. Polyamines and hypusination are required for ebolavirus gene expression and replication. mBio. 2016;7(4):e00882–00816. doi:10.1128/mBio.00882-1627460797

 PubMed Web of Science ®Google Scholar

Guan H, Wang M, Liao C, et al. Identification of aaNAT5b as a spermine N-acetyltransferase in the mosquito, Aedes aegypti. PLoS One. 2018;13(3):e0194499. doi:10.1371/journal.pone.019449929554129

 PubMed Web of Science ®Google Scholar

Mounce BC, Cesaro T, Vlajnić L, et al. Chikungunya virus overcomes polyamine depletion by mutation of nsP1 and the opal stop codon to confer enhanced replication and fitness. J Virol. 2017;91(15):1–45. doi:10.1128/JVI.00344-17

 Web of Science ®Google Scholar

Korovina AN, Tunitskaya VL, Khomutov MA, et al. Biogenic polyamines spermine and spermidine activate RNA polymerase and inhibit RNA helicase of hepatitis C virus. Biochemistry. 2012;77(10):1413–1422. doi:10.1134/S0006297912100094

 Web of Science ®Google Scholar

Smirnova OA, Keinanen TA, Ivanova ON, et al. Hepatitis C virus alters metabolism of biogenic polyamines by affecting expression of key enzymes of their metabolism. Biochem Biophys Res Commun. 2017;483(2):904–909. doi:10.1016/j.bbrc.2017.01.03228082202

 PubMed Web of Science ®Google Scholar

Masalova OV, Lesnova EI, Samokhvalov EI, et al. Low-molecular-weight regulators of biogenic polyamine metabolism affect cytokine production and expression of hepatitis С virus proteins in Huh7.5 human hepatocarcinoma cells. Mol Biol. 2017;51(3):453–464. doi:10.1134/S0026893317030128

 Web of Science ®Google Scholar

Mao B, Wang Z, Pi S, et al. Difluoromethylornithine, a decarboxylase 1 inhibitor, suppresses hepatitis B virus replication by reducing hbc protein levels. Front Cell Infect Microbiol. 2020;10:158. doi:10.3389/fcimb.2020.0015832373551

 PubMed Web of Science ®Google Scholar

Shi M, Gan Y-J, Davis TO, Scott RS. Downregulation of the polyamine regulator spermidine/spermine N1-acetyltransferase by epstein–barr virus in a Burkitt’s lymphoma cell line. Virus Res. 2013;177(1):11–21. doi:10.1016/j.virusres.2013.07.00423891576

 PubMed Web of Science ®Google Scholar

Pozzi B, Bragado L, Mammi P, et al. Dengue virus targets RBM10 deregulating host cell splicing and innate immune response. Nucleic Acids Res. 2020;48(12):6824–6838. doi:10.1093/nar/gkaa34032432721

 PubMed Web of Science ®Google Scholar

Mastrodomenico V, Esin JJ, Graham ML, et al. Polyamine depletion inhibits bunyavirus infection via generation of noninfectious interfering virions. J Virol. 2019;93(14):e00530–00519. doi:10.1128/JVI.00530-1931043534

 PubMed Web of Science ®Google Scholar

Mastrodomenico V, Esin J, Qazi S, et al. Virion-associated polyamines transmit with bunyaviruses to maintain infectivity and promote entry. ACS Infect Dis. 2020;6(9):2490–2501. doi:10.1021/acsinfecdis.0c0040232687697

 PubMed Web of Science ®Google Scholar

Liu J, Henao-Mejia J, Liu H, Zhao Y, He JJ. Translational regulation of HIV-1 replication by HIV-1 rev cellular cofactors Sam68, eIF5A, hRIP, and DDX3. J Neuroimmune Pharmacol. 2011;6(2):308–321. doi:10.1007/s11481-011-9265-821360055

 PubMed Web of Science ®Google Scholar

Hoque M, Hanauske-Abel HM, Palumbo P, et al. Inhibition of HIV-1 gene expression by ciclopirox and deferiprone, drugs that prevent hypusination of eukaryotic initiation factor 5A. Retrovirology. 2009;6(1):90. doi:10.1186/1742-4690-6-9019825182

 PubMed Web of Science ®Google Scholar

Bevec D, Jaksche H, Oft M, et al. Inhibition of HIV-1 replication in lymphocytes by mutants of the rev cofactor eIF-5A. Science. 1996;271(5257):1858–1860. doi:10.1126/science.271.5257.18588596953

 PubMed Web of Science ®Google Scholar

Greco A, Callé A, Morfin F, et al. S-adenosyl methionine decarboxylase activity is required for the outcome of herpes simplex virus type 1 infection and represents a new potential therapeutic target. FASEB J. 2005;19(9):1128–1130. doi:10.1096/fj.04-2108fje15863396

 PubMed Web of Science ®Google Scholar

Pohjanpelto P, Sekki A, Hukkanen V, Bonsdorff C-HV. Polyamine depletion of cells reduces the infectivity of herpes simplex virus but not the infectivity of virus. Life Sci. 1988;42(20):2011–2018. doi:10.1016/0024-3205(88)90501-22835567

 PubMed Web of Science ®Google Scholar

Gibson W, Roizman B. Compartmentalization of spermine and spermidine in the herpes simplex virion. Proc Nat Acad Sci USA. 1971;68(11):2818–2821. doi:10.1073/pnas.68.11.28185288261

 PubMed Web of Science ®Google Scholar

Gibson W, Breemen RV, Fields A, Lafemina R, Irmiere A. D,L-alpha-difluoromethylornithine inhibits human cytomegalovirus replication. J Virol. 1984;50(1):145–154. doi:10.1128/JVI.50.1.145-154.19846321786

 PubMed Web of Science ®Google Scholar

Tyms AS, Williamson JD. Inhibitors of polyamine biosynthesis block human cytomegalovirus replication. Nature. 1982;297(5868):690–691. doi:10.1038/297690a06283366

 PubMed Web of Science ®Google Scholar

Tuomi K, Mantyjarvi R, Raina A. Inhibition of Semliki Forest and herpes simplex virus production in alpha-difluoromethylornithinetreated cells: reversal by polyamines. FEBS Lett. 1980;121(2):292–294. doi:10.1016/0014-5793(80)80365-66257550

 PubMed Web of Science ®Google Scholar

Tuomi K, Rainat A, Mantyjarvi R. Synthesis of Semliki-Forest virus in polyamine-depleted baby-hamster kidney cells. Biochem Soc. 1982;206:113–119.

 Google Scholar