Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity

J.H. Kim, R. Resende, T. Wennekes, N. Chen, N. Bance, S. Buchini, A.G. Watts, P. Pilling, V.A. Streltsov, M. Petric, R. Liggins, S. Barrett, J.L. McKimm-Breschkin, M. Niikura, S.G. Withers

Research output: Contribution to journalArticleAcademicpeer-review

128 Citations (Scopus)

Abstract

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor oseltamivir may limit their future utility. We report here a new class of specific, mechanism-based anti-influenza drugs that function via the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and confirm this mode of action via structural and mechanistic studies. These compounds function in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad spectrum activity against drug-resistant strains in vitro. The similarity of their structure to that of the natural substrate and their mechanism-based design make these attractive antiviral candidates
Original languageEnglish
Pages (from-to)71-75
JournalScience
Volume340
Issue number6128
DOIs
Publication statusPublished - 2013

    Fingerprint

Keywords

  • virus neuraminidase
  • drug design
  • h1n1 virus
  • resistant
  • sialidase
  • 4-guanidino-neu5ac2en
  • sensitivity
  • oseltamivir
  • mutations
  • variant

Cite this

Kim, J. H., Resende, R., Wennekes, T., Chen, N., Bance, N., Buchini, S., ... Withers, S. G. (2013). Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity. Science, 340(6128), 71-75. https://doi.org/10.1126/science.1232552