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Prevention of poxvirus infection by tetrapyrroles
© Chen-Collins et al; licensee BioMed Central Ltd. 2003
Received: 30 October 2002
Accepted: 28 May 2003
Published: 28 May 2003
Prevention of poxvirus infection is a topic of great current interest. We report inhibition of vaccinia virus in cell culture by porphyrins and phthalocyanines. Most previous work on the inhibition of viruses with tetrapyrroles has involved photodynamic mechanisms. The current study, however, investigates light-independent inhibition activity.
The Western Reserve (WR) and International Health Department-J (IHD-J) strains of vaccinia virus were used. Virucidal and antiviral activities as well as the cytotoxicity of test compounds were determined.
Examples of active compounds include zinc protoporphyrin, copper hematoporphyrin, meso(2,6-dihydroxyphenyl)porphyrin, the sulfonated tetra-1-naphthyl and tetra-1-anthracenylporphyrins, selected sulfonated derivatives of halogenated tetraphenyl porphyrins and the copper chelate of tetrasulfonated phthalocyanine. EC50 values for the most active compounds are as low as 0.05 µg/mL (40 nM). One of the most active compounds was the neutral meso(2,6-dihydroxyphenyl)porphyrin, indicating that the compounds do not have to be negatively charged to be active.
Porphyrins and phthalocyanines have been found to be potent inhibitors of infection by vaccinia virus in cell culture. These tetrapyrroles were found to be active against two different virus strains, and against both enveloped and non-enveloped forms of the virus, indicating that these compounds may be broadly effective in their ability to inhibit poxvirus infection.
Smallpox, while not found in the world's population at present, remains a potential health hazard especially due to the possibility of its use as a bioweapon [1–5]. There is currently no accepted treatment for smallpox, although a number of agents have been evaluated . Therefore, new therapeutic or virucidal agents could have great utility in slowing both the progression and spread of the disease in an epidemic situation. In the present study, we have investigated the potential of porphyrins (Por) and phthalocyanines (Pc) to prevent infection by vaccinia virus in cell culture.
Materials and Methods
Porphyrins and phthalocyanines
Porphyrins were obtained from Midcentury Chemicals (Chicago, Illinois) or Frontier Scientific (Logan, Utah) and used as received. Porphyrin designations are as follows: PP, protoporphyrin IX; HP, hematoporphyrin IX; TPP, meso-tetraphenylporphine; TNapPS, sulfonated 5,10,15,20-tetra-naphthalen-1-yl-porphyrin; TAnthPS, sulfonated 5,10,15,20-tetra-anthracen-9-yl-porphyrin. Other porphyrins are tetraphenylporphyrin derivatives, e.g., TPP2F is tetraphenylporphyrin with a fluoro group at the 2-position on each phenyl ring. An "S" at the end of the name indicates that the parent porphyrin was sulfonated. In most cases, these are mixtures with variable numbers of sulfonates and/or positions of the sulfonates on the ring. The sulfonated copper phthalocyanine [sold as CuPcS(3,4',4",4"')] was purchased from Aldrich.
Cell lines and virus strains
CV-1, BSC-40 and TK-143B cells were maintained in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS) and incubated at 37°C, 5% CO2. CV-1 cells were utilized for virus titer determinations and TK-143B cells were used in virus stock preparations. HeLa S3 cells were grown at 37°C in RPMI 1640 culture medium supplemented with 10% FBS and the antibiotics penicillin and streptomycin.
Growth of vaccinia virus (VV)
Two strains of vaccinia virus (VV) were used in this study: the Western Reserve (WR) and International Health Department-J (IHD-J) strains. The WR strain, produced by Virotech International (Rockville, MD), was a gift from Dr. Mark Feinberg (Emory University). The IHD-J strain was grown as described previously . TK-143B cells, grown in roller bottles, were infected with the WR strain of the virus and incubated for 2 days at 37°C. The cells were collected, resuspended in a buffered solution of 10 mM Tris-HCl (pH 9) and homogenized with 20 strokes in a Dounce homogenizer. Large debris and nuclei were sedimented by centrifugation at 1,400 rpm for 5 min. The supernatant was collected and trypsin (250 µg/mL) added. This was then loaded on a 36% sucrose cushion and the virus pelleted by centrifugation at 13,500 rpm for 80 min using a Beckman SW28 rotor. Extracellular particles of IHD-J were obtained by infecting TK-143B cells. After 24 h incubation at 37°C, the culture medium was pre-cleared and the virus was concentrated by centrifugation at 13,500 rpm for 80 min in a SW28 rotor and resuspended in 1 mM Tris-HCl (pH 9).
Prevention of virus infection
A plaque assay was used to determine the ability of test compounds to prevent infection. Compound stock solutions, 5 mg/mL, were diluted 10-fold in DMEM without FBS and mixed with virus particles to five final concentrations: 50, 10, 2, 0.4 and 0.08 µg/mL. After 1 h incubation (in the dark) the virus-drug mixture was diluted 10-fold in DMEM (without FBS) to 500 µL and 100 µL added to each well of confluent CV-1 or BSC-40 cells grown in 24-well plates. This afforded 200 pfu/well (1 × 10-3 pfu/cell). Following virus-drug adsorption onto the monolayer, 1 h at 37°C, cell monolayers were washed twice PBS to remove residual virus-drug mixture. New growth medium supplemented with 2.5% FBS was then added to each well.
A plaque assay was used to determine the quantity of infectious particles remaining after drug treatment. Two days after infection, the growth medium was removed and the cells washed twice with PBS. A solution of 0.1% crystal violet, 10% formaldehyde in phosphate buffered saline (PBS) was then added to the wells. After 30 min incubation, the stain was removed and the wells washed with PBS and allowed to dry. The number of plaques was then determined and activity calculated based on the reduction in average number of plaques, in wells where the compound was pre-incubated with the virus, compared to the control wells inoculated with untreated virus. As an alternative to the liquid overlay, agar overlays were also investigated. Similar results were obtained with both assays. Hence, further plaque assays were done using liquid overlays.
EC50 values were calculated as response = min + (max-min)/(1+10 [exp(log[drug]-logEC50)] using Kaleidagraph (Synergy Software, Reading, Pennsylvania). Reported EC50 values are the average and standard deviation of three separate determinations, each replicated three times.
Inhibition of virus yield
Confluent monolayers of CV-1 cells were infected with 5 × 105 pfu/well (2.5 pfu/cell) of WR for 2 h at 37°C. The cells were then washed twice with PBS to remove any residual virus. Compound stock solutions, 5 mg/mL, were diluted in DMEM with 2.5% FBS to final concentrations of 50 or 25 µg/mL. This media containing compounds (500 µL) was then added to the cells. At 16 h post-infection, cell monolayers and culture medium were harvested and subjected to several cycles of freeze/thawing to release intracellular and extracellular virus particles. A plaque assay on CV-1 cells was used to determine the virus titer. CV-1 cells were infected with the virus inoculum for 1 h; the growth medium was removed and 2.5% FBS in DMEM added to the cells. After 2 days, the cells were washed with PBS and later stained with a solution of 0.1% crystal violet, 10% formaldehyde in PBS, and the viral plaque number was counted. To determine if viral inactivation occurs after cell lysis, the cell monolayers were washed three times with DMEM to remove the compounds then harvested and subjected to several cycles of freeze/thawing to release intracellular virus particles.
Cell proliferation assay
Cell proliferation was measured by [3H]-thymidine uptake . HeLa S3 cells (3 × 104 cells/well) were incubated in 96-well plates in the presence of varying concentrations of the tetrapyrroles for 2 days at 37°C, after which 3H-TdR (1 µCi/well) was added. The cells were further incubated for 16 h, then harvested and 3H-TdR incorporation monitored by using a liquid scintillation counter. Data are from a single experiment.
Cytotoxicity of active tetrapyrroles
CV-1 and BSC-40 cells were seeded at a concentration of 3.5 × 104 cells/well in a 96-well plate and allowed to attach overnight, after which they were ~80% confluent. Compounds in DMEM with 10% FBS were added to the cells. After 2 days, a trypan blue viability assay  was performed. The 50% cytotoxic concentration (CC50) is the concentration required to reduce viable cell numbers by 50% relative to untreated control cell numbers. This was determined by incubation in growth medium containing serial dilutions of compounds in the range of 50 – 2000 µg/mL for 2 days, after which the viable cell numbers were determined. To determine the effect of the compounds on cell proliferation, after 24 h incubation, the cells were washed and further incubated in the absence of the compounds for 1 day, and then a trypan blue assay was done. Data are from a single experiment.
CV-1 cells were seeded at 3.5 × 103 cells/well (in growth medium) in a 96-well plate and allowed to attach overnight; the compounds (in growth medium) were then added. Following a 24 h incubation, the cells were counted.
Prevention of vaccinia virus infection by tetrapyrroles.
15 ± 12
26 ± 3.4
38 ± 7.8
29 ± 13
14 ± 5.3
8.2 ± 1.3
50 ± 7
0.83 ± 0.1
0.71 ± 0.3
1.0 ± 0.1
0.30 ± 0.1
0.15 ± 0.03
0.05 ± 0.0005
0.2 ± 0.1
0.55 ± 0.14
0.17 ± 0.01
0.19 ± 0.03
0.59 ± 0.1
0.7 ± 0.2
0.32 ± 0.11
7.8 ± 0.9
0.03 ± 0.01
1.5 ± 0.4
1.1 ± 0.4
0.32 ± 0.13
1.6 ± 0.1
0.74 ± 0.38
0.44 ± 0.02
6.1 ± 1.6
5.6 ± 2.8
1.0 ± 0.1
1.3 ± 0.4
0.5 ± 0.1
1.0 ± 0.2
1.0 ± 0.1
0.7 ± 0.1
1.3 ± 0.3
0.26 ± 0.1
1.1 ± 0.5
Approximately 25 sulfonated phthalocyanines (PcS) were evaluated. Only the copper and chromium PcS were able to inhibit viral infection. The copper phthalocyanine sulfonate only had an EC50 of approximately 50 µg/mL in the WR assay in both cell lines. It was somewhat more active in the IHD-J assays, but the sulfonated phthalocyanines were not studied further.
Since there are major differences in surface antigens, and presumably in the host cell receptors, between the intracellular and extracellular particles of VV [10–12], we also compared the sensitivity of the two forms to the compounds to be tested. Generally, the compounds tested were highly effective against both forms (Table 1). Comparison of the intracellular mature virion (IMV, third column in Table 1) and extracellular enveloped virion (EEV) forms of the IHD-J strain showed differences in activity of some compounds in blocking infection by the two forms of the virus. These results suggest that the tetrapyrroles may be binding to different components on the surface of the two forms of the virus and thus show differences in efficiency of preventing virus infection.
Therapeutic indices of selected tetrapyrroles.
Effects of tetrapyrroles on cell viability and growth.
Reduction of vaccinia virus yield by selected tetrapyrroles.a
3.5 × 105
2.6 × 105
3.0 × 106
5.8 × 105
1.1 × 106
4.5 × 105
6.3 × 106
4.1 × 106
2.5 × 105
1.0 × 105
Inhibition of virus yield after removal of tetrapyrroles before cell lysis.a
3.5 × 105
73 ± 16
1.0 × 105
92 ± 1
1.2 × 106
39 ± 13
7.5 × 105
67 ± 15
1.3 × 106
33 ± 9
6.3 × 105
71 ± 4
9.3 × 105
49 ± 21
8.3 × 105
59 ± 2
7.2 × 105
65 ± 0.3
6.4 × 105
70 ± 4
Inhibition of virus yield during multiple cycle infection.a
3.3 × 104
87 ± 5
1.3 × 104
95 ± 2
4.7 × 104
81 ± 5
2.7 × 104
89 ± 6
5.0 × 104
80 ± 2
2.3 × 104
91 ± 2
2.1 × 104
92 ± 3
2.4 × 104
90 ± 2
2.1 × 104
92 ± 1
3.2 × 103
99 ± 7
Photoinactivation of viruses by diamagnetic porphyrins and phthalocyanines has been widely studied [13–20]. Photoactivation involves absorption of light by the tetrapyrrole with resulting production of free radicals and singlet oxygen. In the current study, inhibition of vaccinia infection is not due to photoactivation of the tetrapyrroles, as shown by two aspects of the experiments. First, there was little exposure to light during experiments, with no additional irradiation. Second, we observed that the extent of inactivation was not a function of the spin state (diamagnetic or paramagnetic) for metal chelates of the porphyrins and phthalocyanines. Only diamagnetic tetrapyrroles are able to inhibit viruses via photoinactivation; the excited states of the paramagnetic derivatives have short half-lives and do not give significant amounts of free radicals or singlet oxygen. Tetrapyrroles previously have been reported to inhibit certain other viruses by mechanisms not involving photoactivation. A cationic phthalocyanine was reported to inhibit human rhinovirus type 5 (RV-5) infection . Selected porphyrin derivatives inhibit specific viral targets including retroviral reverse transcriptase [22–26] and HIV-1 protease .
In previous studies of the antiviral effects of porphyrins, Song et al. investigated the antiviral effects of Fe meso-tetrakis(3,4-disulfonatomesityl)porphyrin (FeTMPS), and meso-tetra(4-carboxyphenyl)porphyrin (TPPC) and its iron and nickel chelates for a variety of viruses . EC50s were generally 20 µg/mL or greater for VV, VSV, HSV-1, HSV-2, Coxsackie virus B4 and poliovirus-1. FeTMPS showed activity in this range also for parainfluenza-3, reovirus-1, and Semliki forest virus. FeTMPS was more active for sindbis virus, VZV and CMV, with EC50s of 5 to 25 µg/mL. Fe and Ni TPPC were also quite active against CMV.
Porphyrins and metalloporphyrins have also been shown to have antiviral activity against HIV [23–38]. Previous studies indicated that some porphyrins inhibit the interaction between the virus envelope protein and its receptors [28, 31–38]. We have shown also that porphyrins block infection by HIV-1 and that this activity appears to be a result of an interaction with the envelope protein . In this regard, the compounds that were active in blocking infection by HIV-1 tended to be sulfonated compounds or other negatively charged compounds. In the present study, it is of interest that the uncharged molecule TPP[2,6-(OH)2] was one of the most active compounds tested. This result indicates that the activity of this compound with VV is not merely a reflection of an interaction between a negatively charged molecule and positively charged sites on the viral surface, but that other structural features are important for interaction with viral proteins.
Although the WR and IHD-J strains exhibited similar sensitivity to most of the compounds tested, some differences in their relative sensitivity was observed. The WR strain was 3- to 6-fold less sensitive than IHD-J to several compounds including TAnthPS, CuHPIX, and TPP2FS, but was about 3-fold more sensitive to inhibition by TPP[2,6(OH)2]. These results support the conclusion that the compounds block infection by interacting with specific viral protein(s), and that strain-specific differences in protein structures determine the differences in sensitivities to specific compounds. The sensitivity of the activity to relatively small structural changes in our work indicates either that amphiphilicity and steric and specific axial ligand effects significantly control binding to the virion target, or that more than one mechanism of inhibition is operational.
EC50 data obtained from both viruses studied ranged from 0.05 to 40 µM. This range is comparable to that observed for other compounds active against vaccinia. For example, cidofovir, an acyclic nucleoside with activity against a variety of DNA viruses, used clinically in some instances , has been shown to be effective against a number of poxviruses with the following EC50 values: 2.3 µM (camelpox), 46.2 µM (vaccinia), 27 µM (monkeypox) and 58 µM (cowpox) [40, 41]. Other classes of compounds have been tested for their effectiveness against vaccinia virus including the IMP dehydrogenase inhibitors (EC50 4 – 100 µg/mL), OMP decarboxylase inhibitors (0.02 – 15 µg/mL), and polyanionic compounds (0.1 – 20 µg/mL) .
In conclusion, we observed that both porphyrins and phthalocyanines have substantial antiviral activity against vaccinia virus. Examples of the natural porphyrin, sulfonated tetraphenylporphyrin, neutral tetraphenylporphyrin and sulfonated phthalocyanine classes were all found to be active. These results, as well as the high therapeutic ratios observed, indicate that these compounds represent attractive candidates as antiviral agents to control poxvirus infection.
This study was supported by NIH grant AI45883. The authors thank Atia Alam and Dahnide Taylor for technical assistance and Tanya Cassingham for assistance in preparing the manuscript.
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