title: Nonsulfated, cinnamic acid-based lignins are potent antagonists of HSV-1 entry into cells.
abstract: In an effort to discover macromolecular mimetics of heparan sulfate (HS), we previously designed sulfated lignins (Raghuraman et al. Biomacromolecules 2007, 8, 1759-1763). To probe the relevance of sulfate groups of HS in viral entry, lignins completely devoid of sulfate moieties, and yet possessing an electrostatic surface equivalent to that of HS, were designed. Two carboxylated lignins based on a 4-hydroxy cinnamic acid scaffold were synthesized using enzymatic oxidative coupling in high yields, fractionated according to their sizes, and tested in cellular assays of herpes simplex virus-1 (HSV-1) infection. The two carboxylated lignins were found to not only inhibit HSV-1 entry into mammalian cells (IC(50) = 8-56 nM), but were more potent than sulfated lignins. In addition, shorter carboxylated lignins were found to be as active as the longer chains, suggesting that structural features, in addition to carboxylate groups, may be important. It can be expected that carboxylated lignins also antagonize the entry of other enveloped viruses, for example, HIV-1, Kaposi's sarcoma-associated herpes virus, and hepatitis C virus, that utilize HS to gain entry into cells. The results present major opportunities for developing lignin-based antiviral formulations for topical use.
authors.affiliation: Department of Medicinal Chemistry and Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, 800 East Leigh Street, Suite 212, Richmond, Virginia 23219, USA.
authors.forename: Jay N
authors.initials: JN
authors.lastname: Thakkar
authors.forename: Vaibhav
authors.initials: V
authors.lastname: Tiwari
authors.forename: Umesh R
authors.initials: UR
authors.lastname: Desai
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002459:Cell Fusion; D002934:Cinnamates / Q000737:chemistry*; D018259:Herpesvirus 1, Human / Q000502:physiology*; D006801:Humans; D008031:Lignin / Q000737:chemistry / Q000494:pharmacology*; D008970:Molecular Weight
chemical_list: D000998:Antiviral Agents; D002934:Cinnamates; C029010:cinnamic acid; D008031:Lignin
references.citation: Annu Rev Plant Biol. 2003;54:519-46
references.pmid: 14503002
references.citation: Comp Biochem Physiol B Biochem Mol Biol. 2006 Jan;143(1):37-43
references.pmid: 16298150
references.citation: Chem Pharm Bull (Tokyo). 1992 Aug;40(8):2102-5
references.pmid: 1423763
references.citation: Biomacromolecules. 2008 Dec;9(12):3378-82
references.pmid: 18991457
references.citation: J Biol Chem. 2007 Nov 2;282(44):31891-9
references.pmid: 17804413
references.citation: Biol Pharm Bull. 1993 Apr;16(4):434-6
references.pmid: 8358397
references.citation: Mass Spectrom Rev. 2004 Mar-Apr;23(2):87-126
references.pmid: 14732934
references.citation: Curr Med Chem. 2004 Sep;11(18):2399-419
references.pmid: 15379705
references.citation: Phytochemistry. 2009 Jan;70(1):147-55
references.pmid: 19056096
references.citation: Cell. 1996 Nov 1;87(3):427-36
references.pmid: 8898196
references.citation: J Agric Food Chem. 2003 Feb 12;51(4):981-6
references.pmid: 12568559
references.citation: Biomacromolecules. 2007 May;8(5):1759-63
references.pmid: 17439173
references.citation: J Agric Food Chem. 1999 Aug;47(8):3325-31
references.pmid: 10552653
references.citation: J Agric Food Chem. 2008 Nov 12;56(21):10368-75
references.pmid: 18841901
references.citation: Biomacromolecules. 2005 Sep-Oct;6(5):2822-32
references.pmid: 16153124
references.citation: J Biol Chem. 2001 Jun 1;276(22):18734-41
references.pmid: 11278569
references.citation: Curr Pharm Des. 2009;15(25):2946-57
references.pmid: 19754371
references.citation: Virology. 2010 Feb 20;397(2):389-98
references.pmid: 20004926
references.citation: Biosci Biotechnol Biochem. 1999 Dec;63(12):2202-4
references.pmid: 10664853
references.citation: Cell. 1999 Oct 1;99(1):13-22
references.pmid: 10520990
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2003 Dec;136(4):357-65
references.pmid: 15012907
references.citation: Tetrahedron. 2010 Apr 17;66(16):2907-2918
references.pmid: 20689724
references.citation: Virology. 1998 Jun 20;246(1):179-89
references.pmid: 9657005
references.citation: Virol Sin. 2008 Dec 1;23(6):383-393
references.pmid: 19956628
references.citation: Bioorg Med Chem. 2006 Dec 1;14(23):7988-98
references.pmid: 16914317
references.citation: J Gen Virol. 2004 Apr;85(Pt 4):805-809
references.pmid: 15039523
references.citation: Tetrahedron Lett. 2007 Sep 17;48(38):6754-6758
references.pmid: 18797498
references.citation: Org Biomol Chem. 2003 Jan 21;1(2):268-81
references.pmid: 12929422