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

Published Online February 21 2013
< Science Express Index

 Read Full Text for Comments (0)

Science DOI: 10.1126/science.1232552

• Report

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

1. Jin-Hyo Kim¹,*,^†,
2. Ricardo Resende¹,*,
3. Tom Wennekes¹,*,^‡,
4. Hong-Ming Chen¹,*,
5. Nicole Bance²,
6. Sabrina Buchini¹,^§,
7. Andrew G. Watts³,
8. Pat Pilling⁴,
9. Victor A. Streltsov⁴,
10. Martin Petric⁵,
11. Richard Liggins⁶,
12. Susan Barrett⁴,
13. Jennifer L. McKimm-Breschkin⁴,
14. Masahiro Niikura²,
15. Stephen G. Withers¹,||

+ Author Affiliations

1. ¹Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T1Z1, Canada.
2. ²Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, B.C., V5A1S6, Canada.
3. ³Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA27AY, UK.
4. ⁴CSIRO Materials Science and Engineering, 343 Royal Pde, Parkville, 3052, Australia.
5. ⁵British Columbia Centre for Disease Control, Provincial Health Services Authority, Vancouver, BC, V5Z 4R4, Canada.
6. ⁶Centre for Drug Research and Development (CDRD), 2259 Lower Mall, Vancouver, B.C., V6T 1Z4, Canada.

+ Author Notes

• ↵† Present address: Division of Chemical Safety, National Academy of Agricultural Science, RDA, 126 Suin-ro, Suwon, 441-707, Republic of Korea.
• ↵‡ Present address: Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB Wageningen, The Netherlands.
• ↵§ Present address: Nano Bridging Molecules SARte Cité-Ouest 2,CH-1196 Gland, Switzerland.

1. ↵^||To whom correspondence should be addressed. E-mail: withers@chem.ubc.ca

1. ↵* These authors contributed equally to this work.

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.

• Received for publication 9 November 2012.
• Accepted for publication 13 February 2013.