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Pentavalent Sialic Acid Conjugates Block Coxsackievirus A24 Variant and Human Adenovirus Type 37-Viruses That Cause Highly Contagious Eye Infections
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.
Umeå universitet, Teknisk-naturvetenskapliga fakulteten, Kemiska institutionen.ORCID-id: 0000-0001-5912-8429
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Avdelningen för virologi.
Vise andre og tillknytning
2020 (engelsk)Inngår i: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 15, nr 10, s. 2683-2691Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Coxsackievirus A24 variant (CVA24v) and human adenovirus 37 (HAdV-37) are leading causative agents of the severe and highly contagious ocular infections acute hemorrhagic conjunctivitis and epidemic keratoconjunctivitis, respectively. Currently, neither vaccines nor antiviral agents are available for treating these diseases, which affect millions of individuals worldwide. CVA24v and HAdV-37 utilize sialic acid as attachment receptors facilitating entry into host cells. Previously, we and others have shown that derivatives based on sialic acid are effective in preventing HAdV-37 binding and infection of cells. Here, we designed and synthesized novel pentavalent sialic acid conjugates and studied their inhibitory effect against CVA24v and HAdV-37 binding and infection of human corneal epithelial cells. The pentavalent conjugates are the first reported inhibitors of CVA24v infection and proved efficient in blocking HAdV-37 binding. Taken together, the pentavalent conjugates presented here form a basis for the development of general inhibitors of these highly contagious ocular pathogens.

sted, utgiver, år, opplag, sider
American Chemical Society (ACS), 2020. Vol. 15, nr 10, s. 2683-2691
HSV kategori
Identifikatorer
URN: urn:nbn:se:umu:diva-176796DOI: 10.1021/acschembio.0c00446ISI: 000582580100008PubMedID: 32845119Scopus ID: 2-s2.0-85093538705OAI: oai:DiVA.org:umu-176796DiVA, id: diva2:1503320
Tilgjengelig fra: 2020-11-24 Laget: 2020-11-24 Sist oppdatert: 2023-03-24bibliografisk kontrollert
Inngår i avhandling
1. Tailored conjugates of N-acetylneuraminic acid and small molecules that block virus cell attachment and entry
Åpne denne publikasjonen i ny fane eller vindu >>Tailored conjugates of N-acetylneuraminic acid and small molecules that block virus cell attachment and entry
2021 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Viruses are obligate intracellular parasites, unable to replicate without exploiting machinery andmaterials from host cells. Pandemics of viral diseases have had large impacts on human socieities and are continued threats to global health. The most efficient means of controlling viral diseases are preventive measures such as immunization of the population, social distancing, and basic hygiene routines. Another mean is development of antiviral drugs that could be used as preventive measures and in treatment of infected individuals. Coxsackievirus A24 variant (CVA24v) is a highly contagious pathogen that cause large outbreaks and pandemics of the eye infection acute hemorrhagic conjunctivitis. Human adenovirus D species type 37 (HAdV-D37) causes epidemics of the severe eye infection epidemic keratoconjunctivitis, that can become life-threatening in immunocompromised individuals. Currently, no specific treatments (vaccine or antivirals) are available to combat the diseases caused by these two pathogens.

CVA24v and HAdV-D37 bind to N-acetylneuraminic acid (Neu5Ac) glycans on host cells facilitating attachment and subsequent infection. In this thesis, we explored inhibition of this common recognition motif by development of pentavalent Neu5Ac containing molecules with radial topology to act as decoy receptors. This allowed us to study the potential of development of a general inhibitor targeting both these viruses. The developed compounds inhibited attachment of CVA24v and HAdVD37 to cells.

Furthermore, we developed divalent Neu5Ac tools to validate if targeting the Neu5Acmediated attachment of CVA24v to cells were a potential target for antiviral drug discovery and development. The results from these studies indicate that development of a Neu5Ac-based antiviral targeting CVA24v looks bleak as the primary receptor utilized by this virus is ICAM-1. The work with developing Neu5Ac tools led to a side project with synthesis of 4-O-alkyl Neu5Ac analogs. In this project we provided a method to synthesize 4-O-alkyl analogs of Neu5Ac and gave insights into the scope of the reaction. This work could have have value in drug discovery.

Targeting enterovirus uncoating is a well explored strategy for the inhibition of enterovirus infection. In this thesis, we synthezied novel branched probes of pleconaril (a well-known pocket binding molecule) to study if targeting the unique branched pocket of CVA24v could have potential as a target for antiviral drug discovery. Further experiments are needed to draw conclusions in regards to the future prospects of targeting this unique feature.

At last, two novel classes of trivalent Neu5Ac conjugates were develop using a structure-based approach targeting HAdV-D37, -D36, and -D26. This led to a more potent compound towards HAdVD37 further validating that targeting the attachment of this virus to cells is a reasonable strategy for antiviral drug development. Towards HAdV-D26 the inhibitory effect was saturated at 50%, likely due to engagement of other receptors. Evaluation towards HAdV-D36 is currently ongoing. Structural biology studies, indicates the compounds bind to the viruses via chelation of their trimeric binding sites. Taken together, these compounds have potential to be used as chemical tools to study the biology of human adenoviruses and perhaps other Neu5Ac binding proteins.

sted, utgiver, år, opplag, sider
Umeå: Umeå Universitet, 2021. s. 91
Emneord
N-acetylneuraminic acid, Neu5Ac, sialic acid, multivalency, Coxsackievirus A24v (CVA24v), Human adenovirus D37, D36, D26, (HAdV-D37, HAdV-D26, HAdV-D36), 4-O-alkyl Neu5Ac, cryo-EM, branched pleconaril probes, conjunctivitis
HSV kategori
Forskningsprogram
organisk kemi
Identifikatorer
urn:nbn:se:umu:diva-182411 (URN)978-91-7855-567-3 (ISBN)978-91-7855-566-6 (ISBN)
Disputas
2021-05-21, KBC Glasburen, Kemiskt Biologiskt Centrum, Umeå, 09:00 (engelsk)
Opponent
Veileder
Merknad

Titel på omslaget: Tailored conjugates of N-acetylneuraminic acid and small molecules that block virus attachment and entry

Tilgjengelig fra: 2021-04-30 Laget: 2021-04-21 Sist oppdatert: 2023-03-16bibliografisk kontrollert

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