Bifunctional Polymeric Inhibitors of Human Influenza A Viruses
Purpose: New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses....
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | en_US |
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Springer Science + Business Media B.V.
2012
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| Online Access: | http://hdl.handle.net/1721.1/73085 https://orcid.org/0000-0003-3830-714X https://orcid.org/0000-0002-5687-6154 |
| _version_ | 1826217968772579328 |
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| author | Haldar, Jayanta Alvarez de Cienfuegos, Luis Tumpey, Terrence M. Gubareva, Larisa V. Chen, Jianzhu Klibanov, Alexander M. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Haldar, Jayanta Alvarez de Cienfuegos, Luis Tumpey, Terrence M. Gubareva, Larisa V. Chen, Jianzhu Klibanov, Alexander M. |
| author_sort | Haldar, Jayanta |
| collection | MIT |
| description | Purpose:
New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses.
Methods:
Individually or together, 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1 + 2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay.
Results:
Attaching 1 to the polymer improved at best millimolar IC50 values over three orders of magnitude. While 2 exhibited micromolar IC50 values, poly-2 was >100-fold even more potent. The IC50 of poly-(1 + 2) against the wild-type strain was >300-fold and ∼17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1 + 2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2.
Conclusions:
The bifunctional poly-(1 + 2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2. |
| first_indexed | 2024-09-23T17:11:34Z |
| format | Article |
| id | mit-1721.1/73085 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T17:11:34Z |
| publishDate | 2012 |
| publisher | Springer Science + Business Media B.V. |
| record_format | dspace |
| spelling | mit-1721.1/730852022-09-30T00:20:22Z Bifunctional Polymeric Inhibitors of Human Influenza A Viruses Haldar, Jayanta Alvarez de Cienfuegos, Luis Tumpey, Terrence M. Gubareva, Larisa V. Chen, Jianzhu Klibanov, Alexander M. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Biology Massachusetts Institute of Technology. Department of Chemistry Koch Institute for Integrative Cancer Research at MIT Klibanov, Alexander M. Alvarez de Cienfuegos, Luis Chen, Jianzhu Purpose: New antiviral agents were prepared by attaching derivatives of sialic acid (1) and of the drug zanamivir (2) to poly(isobutylene-alt-maleic anhydride) (poly-(1 + 2)) or by mixing poly-1 and poly-2, followed by assaying them against wild-type and drug-resistant influenza A Wuhan viruses. Methods: Individually or together, 1 and 2 were covalently bonded to the polymer. The antiviral potencies of the resultant poly-1, poly-2, poly-(1 + 2), and poly-1 + poly-2, as well as 1 and 2, were assessed using plaque reduction assay. Results: Attaching 1 to the polymer improved at best millimolar IC50 values over three orders of magnitude. While 2 exhibited micromolar IC50 values, poly-2 was >100-fold even more potent. The IC50 of poly-(1 + 2) against the wild-type strain was >300-fold and ∼17-fold better than of poly-1 and poly-2, respectively. In contrast, the potency of poly-(1 + 2) vs. poly-2 against the mutant strain merely doubled. The mixture of poly-1 + poly-2 inhibited both viral strains similarly to poly-2. Conclusions: The bifunctional poly-(1 + 2) acts synergistically against the wild-type influenza virus, but not against its drug-resistant mutant, as compared to a physical mixture of the monofunctional poly-1 and poly-2. National Institutes of Health (U.S.) (NIH grant U01-AI074443) Fundación Ramón Areces (postdoctoral fellowship) 2012-09-20T19:24:03Z 2012-09-20T19:24:03Z 2010-02 2009-09 Article http://purl.org/eprint/type/JournalArticle 0724-8741 1573-904X http://hdl.handle.net/1721.1/73085 Haldar, Jayanta et al. “Bifunctional Polymeric Inhibitors of Human Influenza A Viruses.” Pharmaceutical Research 27.2 (2009): 259–263. Web. https://orcid.org/0000-0003-3830-714X https://orcid.org/0000-0002-5687-6154 en_US http://dx.doi.org/10.1007/s11095-009-0013-1 Pharmaceutical Research Creative Commons Attribution-Noncommercial-Share Alike 3.0 http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Springer Science + Business Media B.V. PMC |
| spellingShingle | Haldar, Jayanta Alvarez de Cienfuegos, Luis Tumpey, Terrence M. Gubareva, Larisa V. Chen, Jianzhu Klibanov, Alexander M. Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title | Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title_full | Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title_fullStr | Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title_full_unstemmed | Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title_short | Bifunctional Polymeric Inhibitors of Human Influenza A Viruses |
| title_sort | bifunctional polymeric inhibitors of human influenza a viruses |
| url | http://hdl.handle.net/1721.1/73085 https://orcid.org/0000-0003-3830-714X https://orcid.org/0000-0002-5687-6154 |
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