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A Potent Trivalent Sialic Acid Inhibitor of Adenovirus Type 37 Infection of Human Corneal Cells
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen. Umeå universitet, Medicinska fakulteten, Umeå Centre for Microbial Research (UCMR). Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Virologi. Umeå universitet, Medicinska fakulteten, Molekylär Infektionsmedicin, Sverige (MIMS).
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2011 (Engelska)Ingår i: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 50, nr 29, s. 6519-6521Artikel i tidskrift (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
Wiley , 2011. Vol. 50, nr 29, s. 6519-6521
Nyckelord [en]
adenoviruses, antiviral agents, crystal-structure elucidation, sialic acids, surface plasmon resonance
Nationell ämneskategori
Kemi
Identifikatorer
URN: urn:nbn:se:umu:diva-45043DOI: 10.1002/anie.201101559PubMedID: 21648036OAI: oai:DiVA.org:umu-45043DiVA, id: diva2:425801
Tillgänglig från: 2011-06-22 Skapad: 2011-06-20 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. Early host cell interactions and antivirals against ocular adenoviruses
Öppna denna publikation i ny flik eller fönster >>Early host cell interactions and antivirals against ocular adenoviruses
2015 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[sv]
Tidiga värd cells interaktioner och antiviraler mot okulära adenovirus
Abstract [en]

Viruses are common causative agents of ocular infection among humans. Epidemic keratoconjuntivitis (EKC) is a severe and contagious ocular disease with reported outbreaks worldwide. It is estimated that this disease affects 20-40 million individuals every year, which leads to huge socioeconomic costs for the affected countries. EKC is characterized by keratitis and conjunctivitis but is also associated with pain, edema, lacrimation, and decreased vision that can prolong for months after the infection and in rare cases years. This disease is caused by human adenoviruses (HAdVs), which belong to the family of Adenoviridae. Currently, there is no available treatment against EKC.

EKC is mainly caused by HAdV-8, HAdV-19, HAdV-37, HAdV-53, HAdV-54, and HAdV-56, which belong to species D HAdVs. HAdV-8, HAdV-19 and HAdV-37 have previously been shown to use sialic acid (SA)-containing glycans as cellular receptors to bind to and infect human corneal epithelial (HCE) cells. To characterize the receptor in more detail, we performed a glycan array, which included SA-containing glycans. A branched hexasaccharide terminating with SA in each arm was identified as a candidate receptor. This glycan corresponds to the glycan motif found on a ganglioside, GD1a. By performing a series of biological and biochemical experiments we confirmed the function of the GD1a glycan as a cellular receptor for EKC-causing HAdVs. However, the glycan used as a receptor was linked to plasma membrane protein(s) through O-glycosidic bonds, rather than to a lipid (as in the ganglioside). X-ray crystallography analysis showed that the two terminal SA:s interacted with two of the three previously identified SA-binding sites on the knob domain of the HAdV-37 capsid protein known as the fiber.

Based on the structural features of the GD1a:HAdV-37 knob interaction, we assumed that a three-armed molecule with each arm terminating with SA would be an efficient inhibitor. Such molecules were designed, synthesized and found to efficiently prevent HAdV-37 binding to and infection of corneal cells. These results indicate that trisialic acids-containing compounds may be used for treatment of EKC.

After binding to its primary receptor, most HAdVs have been shown to interact with αVβ3 and αVβ5 integrins to enter human cells. This interaction occurs through the RGD (arginine-alanine-aspartic acid) motif in the capsid protein known as the penton base. However, it was not clear if corneal epithelial cells express αVβ3 and αVβ5 integrins. Thus, to better understand additional early steps of infection by EKC-causing HAdVs, we performed binding and infection competition experiments using human corneal epithelial cells and siRNA, integrin specific antibodies, peptides and RGD-containing ligands indicating that α3, αV, β1 affected HAdV-37 infection of but not binding to HCE cells. We could also see that HAdV-37 co-localize with α3 and αV at after entry into HCE cells. In situ histochemistry confirmed that the expression of α3 and αV in human corneal tissue. Overall, our results suggest that αV and α3 integrins are important for HAdV-37 infection of corneal cells.

Altogether, these results provide further insight into the biology of HAdVs and open up for development of novel antiviral drugs.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå University, 2015. s. 90
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1697
Nyckelord
Adenovirus, Virus host interactions, Antivirals, Sialic acid, Integrins, Epidemic keratoconjuntivitis
Nationell ämneskategori
Mikrobiologi inom det medicinska området
Identifikatorer
urn:nbn:se:umu:diva-99907 (URN)978-91-7601-211-6 (ISBN)
Disputation
2015-03-13, Hörsal Betula, 6M, Norrlands universitetssjukhus, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2015-02-20 Skapad: 2015-02-16 Senast uppdaterad: 2018-06-07Bibliografiskt granskad

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Spjut, SaraQian, WeixingStorm, RickardFrängsmyr, LarsArnberg, NiklasElofsson, Mikael
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Kemiska institutionenUmeå Centre for Microbial Research (UCMR)Molekylär Infektionsmedicin, Sverige (MIMS)Virologi
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