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Design and Synthesis of Sialic Acid Conjugates as Inhibitors of EKC-causing Adenoviruses
Umeå University, Faculty of Science and Technology, Chemistry.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The combat against viral diseases has been, and still is, a major challenge in the field of drug development. Viruses are intracellular parasites that use the host cell ma-chinery for their replication and release. Therefore it is difficult to target and destroy the viral particle without disturbing the essential functions of the host cell. This thesis describes studies towards antiviral agents targeting adenovirus type 37 (Ad37), which causes the severe ocular infection epidemic keratoconjunctivitis (EKC). Cell surface oligosaccharides serve as cellular receptors for many pathogens, including viruses and bacteria. For EKC-causing adenoviruses, cell surface oligo-saccharides with terminal sialic acid have recently been shown to be critical for their attachment to and infection of host cells. The work in this thesis support these re-sults and identifies the minimal binding epitope for viral recognition. As carbo-hydrate–protein interactions in general, the sialic acid–Ad37 interaction is very weak. Nature overcomes this problem and vastly improves the binding affinity by presenting the carbohydrates in a multivalent fashion. Adenoviruses interact with their cellular receptors via multiple fiber proteins, whereby it is likely that the ideal inhibitor of adenoviral infections should be multivalent. This thesis includes design and synthesis of multivalent sialic acid glycoconjugates that mimic the structure of the cellular receptor in order to inhibit adenoviral attachment to and infection of human corneal epithelial (HCE) cells. Synthetic routes to three different classes of sialic acid conjugates, i.e. derivatives of sialic acid, 3’-sialyllactose and N-acyl modified sialic acids, and their multivalent counterparts on human serum albumine (HSA) have been developed. Evaluation of these conjugates in cell binding and cell infectivity assays revealed that they are effective as inhibitors. Moreover the results verify the hypothesis of the multivalency effect and clearly shows that the power of inhibition is significantly increased with higher orders of valency. Potential inhibi-tors could easily be transferred to the eye using a salve or eye drops, and thereby they would escape the metabolic processes of the body, a major drawback of using carbohydrates as drugs. The results herein could therefore be useful in efforts to develop an antiviral drug for treatment of EKC.

Place, publisher, year, edition, pages
Umeå: Kemi , 2008. , 84 p.
Keyword [en]
Sialic acid, sialylmimetics, sialylation, multivalency, glycoconjugates, adenovirus, antiviral agents, epidemic keratoconjunctivitis
National Category
Organic Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-1641ISBN: 978-91-7264-545-5 (print)OAI: oai:DiVA.org:umu-1641DiVA: diva2:141663
Public defence
2008-05-30, KB3B1, KBC, KBC-Huset, Umeå Univeristet, Umeå, 10:00 (English)
Opponent
Supervisors
Available from: 2008-05-08 Created: 2008-05-08 Last updated: 2009-06-23Bibliographically approved
List of papers
1. Multivalent HSA conjugates of 3 '-siallyllactose are potent inhibitors of adenoviral cell attachment and infection
Open this publication in new window or tab >>Multivalent HSA conjugates of 3 '-siallyllactose are potent inhibitors of adenoviral cell attachment and infection
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2005 (English)In: ChemBioChem (Print), ISSN 1439-4227, E-ISSN 1439-7633, Vol. 6, no 2, 358-364 p.Article in journal (Refereed) Published
Abstract [en]

Adenoviruses of serotypes 8, 19 and 37 are the major cause of the severe eye infection EKC (epidemic keratoconjunctivitis). In general, all adenoviruses interact with their cellular receptors through the fibre proteins, which extend from the virus particle. Recently, adenovirus type 37 (Ad37) was found to bind and infect human corneal cells through attachment to carbohydrate structures that carry terminal alpha-(2-3)-linked sialic acids. Herein we present a synthetic route to a 3'-sialyllactose derivative and corresponding multivalent HSA conjugates with varying orders of valency. The potential of these compounds as inhibitors of EKC causing adenovirus of serotype Ad37, was studied with both binding assay and an infectivity assay. The results revealed that these compounds effectively prevent Ad37 from binding to and infecting human corneal epithelial (HCE) cells. Moreover, the inhibition is significantly increased with higher orders of multivalency.

Keyword
antiviral agents, glycoconjugates, glycosylation, multivalency, sialic acids
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) Pharmacology and Toxicology
Identifiers
urn:nbn:se:umu:diva-13606 (URN)10.1002/cbic.200400227 (DOI)000226957100017 ()
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2013-10-31Bibliographically approved
2. Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells
Open this publication in new window or tab >>Multivalent sialic acid conjugates inhibit adenovirus type 37 from binding to and infecting human corneal epithelial cells
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2007 (English)In: Antiviral Research, ISSN 0166-3542, E-ISSN 1872-9096, Vol. 73, no 2, 92-100 p.Article in journal (Refereed) Published
Abstract [en]

Adenovirus type 37 is one of the main causative agents of epidemic keratoconjunctivitis. In a series of publications, we have reported that this virus uses sialic acid as a cellular receptor. Here we demonstrate in vitro that on a molar basis, multivalent sialic acid conjugated to human serum albumin prevents adenovirus type 37 from binding to and infecting human corneal epithelial cells 1000-fold more efficiently than monosaccharidic sialic acid. We also demonstrate that the extraordinary inhibitory effect of multivalent sialic acid is due to the ability of this compound to aggregate virions. We conclude that multivalent sialic acid may be a potential new antiviral drug, for use in the treatment of epidemic keratoconjunctivitis caused by the adenoviruses that use sialic acid as cellular receptor.

Keyword
Adenovirus, EKC, Sialic acid, Multivalent
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-12970 (URN)10.1016/j.antiviral.2006.08.004 (DOI)
Available from: 2007-05-11 Created: 2007-05-11 Last updated: 2011-04-18Bibliographically approved
3. Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenoviruses
Open this publication in new window or tab >>Design, synthesis and evaluation of N-acyl modified sialic acids as inhibitors of EKC-causing adenoviruses
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(English)Manuscript (preprint) (Other academic)
Identifiers
urn:nbn:se:umu:diva-3172 (URN)
Available from: 2008-05-08 Created: 2008-05-08 Last updated: 2011-04-15Bibliographically approved

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Johansson, Susanne

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