Pentavalent sialic acid conjugates inhibit viruses that cause highly contagious eye infections

Session: 
S6.4 Viral glycans
Code: 
OL6.4.4
Location (hall): 
Fucose
Start/end time: 
Tuesday, July 2, 2019 - 18:00 to 18:15
Emil
Johansson

Emil Johansson1, Rémi Caraballo1, Georg Zocher2, Weixing Qian1, Nitesh Mistry3, Niklas Arnberg3, Thilo Stehle2, Mikael Elofsson1

1Umeå University - Department of Chemistry, Umeå, Sweden, 2University of Tübingen, Tübingen, Germany, 3Umeå University - Microbiology, Division of Virology, Umeå, Sweden

Members of the Adenoviridae (Ad8, Ad19, Ad37) and Picornaviridae (enterovirus 70 and Coxsackievirus A24 variant) families are responsible for causing the highly contagious eye infections epidemic keratoconjuctivitis (EKC), and acute hemorrhagic conjunctivitis (AHC), respectively.¹,² The infections are generally self-limiting and spontaneously resolve in 1-2 weeks. However, symptoms may be severe and AHC can result in neurological impairments such as acute flaccid paralysis, and EKC-causing adenoviruses are potentially life-threatening in immunocompromised individuals.²,³,⁴ To date, no antiviral agents or vaccines are available for treating adenovirus and picornavirus infections.⁵

Coxsackievirus A24 variant (CVA24v) has been reported as the main causative agent of AHC. To facilitate attachment, CVA24v binds to glycans terminating in 5-N-acetylneuraminic acid (sialic acid) via recognition sites that cluster in a pentameric geometry around the five-fold symmetry axis of the viral capsid.² Thus, we hypothesized novel pentavalent sialic acid conjugates could effectively chelate the sialic acid binding sites of the virion thereby blocking access to epitopes on host cells. The design is heavily inspired by ME0462, a potent trivalent sialic acid attachment inhibitor of Ad37.⁶ Biological data indicates that the novel pentavalent sialic acid conjugates inhibit infection of human corneal epithelial cells by CVA24v (IC50 10-160 µM), and x-ray crystallography confirmed binding to the virion. Interestingly, the pentavalent sialic acid conjugates are highly efficient inhibitors of Ad37 (IC50 18-190 nM) supporting development of general inhibitors for two of the major causative agents EKC and AHC.

References: 
  1. Aoki, K.; Tagawa, Y. 2000. Internat. Ophtham. Clin. 42(1): 49-54.
  2. Zocher, G.; Mistry, N.; Frank, M.; Hähnlein-Schick, I.; Ekström, J.O.; Arnberg, N.; Stehle, T. 2014. PLOS Path. 10(10): e1004401
  3. de Jong J C, Wermenbol A G, Verweij-Uijterwaal M W, Slaterus K W, Wertheim-van Dillen P, van Doornum G J J, Khoo S H, Hierholzer J C. 1999. J Clin Microbiol. 37: 3940–3945.
  4. Khan A , Sharif S , Shaukat S , Khan S , Zaidi S. 2008. Vir. Res. 137(1):150-152.
  5. Kinchington P. R.; Romanowski E. G.; Gordon Y. J. 2005. Prospects for adenoviral antivirals. J. Antimicrob. Chemother. 55: 424–429.
  6. Caraballo, R., Saleeb, M., Bauer, J., Liaci, A.M., Chandra, N., Storm, R.J., Frängsmyr, L., Qian, W., Stehle, T., Arnberg, N., Elofsson, M. 2015. Org. Biomol. Chem. 13(35): 9194-205.

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