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Sci Rep
2023 Mar 23;131:4804. doi: 10.1038/s41598-023-31722-5.
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Antiviral activity of marine sulfated glycans against pathogenic human coronaviruses.
Zoepfl M
,
Dwivedi R
,
Kim SB
,
McVoy MA
,
Pomin VH
.
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Great interest exists towards the discovery and development of broad-spectrum antivirals. This occurs due to the frequent emergence of new viruses which can also eventually lead to pandemics. A reasonable and efficient strategy to develop new broad-spectrum antivirals relies on targeting a common molecular player of various viruses. Heparan sulfate is a sulfated glycosaminoglycan present on the surface of cells which plays a key role as co-receptor in many virus infections. In previous work, marine sulfated glycans (MSGs) were identified as having antiviral activities. Their mechanism of action relies primarily on competitive inhibition of virion binding to heparan sulfate, preventing virus attachment to the cell surface prior to entry. In the current work we used pseudotyped lentivirus particles to investigate in a comparative fashion the inhibitory properties of five structurally defined MSGs against SARS-CoV-1, SARS-CoV-2, MERS-CoV, and influenza A virus (IAV). MSGs include the disaccharide-repeating sulfated galactan from the red alga Botryocladia occidentalis, the tetrasaccharide-repeating sulfated fucans from the sea urchin Lytechinus variegatus and from the sea cucumber Isostichopus badionotus, and the two marine fucosylated chondroitin sulfates from the sea cucumbers I. badionotus and Pentacta pygmaea. Results indicate specificity of action against SARS-CoV-1 and SARS-CoV-2. Curiously, the MSGs showed decreased inhibitory potencies against MERS-CoV and negligible action against IAV. Among the five MSGs, the two sulfated fucans here studied deserve further attention since they have the lowest anticoagulant effects but still present potent and selective antiviral properties.
Figure 1. Structural representations of HS, heparin and the five MSGs studied. (A) HS is composed of [-4)-N-acetylglucosamine-(α1-4)-glucuronic acid-(α1-]. (B) Heparin is composed of [-4)-N,6-disulfated-glucosamine-(α1-4)-2-sulfated-iduronic acid-(α1-] with additional modifications as indicated in the panel. (C) BoSG is composed of [-3)-galactose-(β1-4)-galactose-(α1-]n with variable sulfation patterns as indicated in the panel. (D) LvSF is composed of [-3)-2,4-disulfated-fucose-(α1-3)-2-sulfated-fucose-(α1-3)-2-sulfated-fucose-(α1-3)-4-sulfated-fucose-(α1-]n. (E) IbSF is composed of [-3)-2,4-disulfated-fucose-(α1-3)-2-disulfated-fucose-(α1-3)-2-sulfated-fucose-(α1-3)- fucose-(α1-]n. (F) IbFucCS is composed of {-4)-[ fucose-(α1-3)]-glucuronic acid-(β1-3)-N-acetylgalactosamine-(β1-} with variable sulfation patterns as indicated. (G) PpFucCS is composed of {-β3)-N-acetylgalactosamine-X-(β1-4)-glucuronic acid-[(3–1)-Y]-(1-}, where X = 4S (80%), 6S (10%) or non-sulfated (10%), Y = α-Fuc2,4S (40%), Fuc2,4S-(α-1–4)-α-Fuc (30%), or α-Fuc4S (30%), and S = SO3−, as indicated in the panel.
Figure 2. Antiviral activity of MSGs against SARS-CoV-1 and SARS-CoV-2. Anti-SARS-CoV-1 (blue) or anti-SARS-CoV-2 (black) activities were measured by incubating HEK-293T-hACE2 cell monolayers in 384-well plates with MSGs for one h, adding VLPs pseudotyped with spike from SARS-CoV-1 or SARS-CoV-2, and measuring GFP 2 days after infection. Cytotoxicity (red) was measured in replicate uninfected cultures treated for 2 days using the CellTiter-Glo® assay. Data were normalized to % maximum RFU and represent means of three independent experiments ± standard deviations.
Figure 3. Antiviral activity of MSGs against MERS-CoV. Anti-MERS-CoV activity (black) and cytotoxicity (red) were measured as described in Fig. 2, except using MERS-CoV spike-pseudotyped VLPs and HeLa-DPP4 cells.
Figure 4. Antiviral activity of MSGs against IAV. Anti-IAV activity (black) and cytotoxicity (red) were measured as described in Fig. 2, except using IAV HA-pseudotyped VLPs and HEK-293T cells.
Figure 5. Time of addition studies. (A–C) Confluent HEK-293T-hACE2 monolayers were treated with 150 µg/mL heparin or MSGs 1 h before, concurrent with, or at various times after addition of VLPs pseudotyped with spike proteins from SARS-CoV-1 (A), SARS-CoV-2 (B), or MERS-CoV (C). GFP expression was quantified 2 days after VLPs were added. Data are means of triplicate wells ± standard deviations. (D) Confluent HEK-293T or HEK-293T-hACE2 monolayers were treated with medium (Ø), 300 µg/mL soluble ACE2 (sACE2), or 150 µg/mL heparin or MSGs either 1 h before or 1 h after addition of VLPs pseudotyped with spike proteins from SARS-CoV-1 or SARS-CoV-2. Representative fluorescent images were captured after incubation for 48 h. Treat and remove indicates replicate cultures that were treated as above for one h and then washed three times with medium prior to addition of VLPs.
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