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Editor, Senior Moderator
Published Online February 21 2013
Science DOI: 10.1126/science.1232552
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Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity
Jin-Hyo Kim1,*,?,
Ricardo Resende1,*,
Tom Wennekes1,*,?,
Hong-Ming Chen1,*,
Nicole Bance2,
Sabrina Buchini1,?,
Andrew G. Watts3,
Pat Pilling4,
Victor A. Streltsov4,
Martin Petric5,
Richard Liggins6,
Susan Barrett4,
Jennifer L. McKimm-Breschkin4,
Masahiro Niikura2,
Stephen G. Withers1,||
+ Author Affiliations
1Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T1Z1, Canada.
2Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, B.C., V5A1S6, Canada.
3Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA27AY, UK.
4CSIRO Materials Science and Engineering, 343 Royal Pde, Parkville, 3052, Australia.
5British Columbia Centre for Disease Control, Provincial Health Services Authority, Vancouver, BC, V5Z 4R4, Canada.
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 Cit?-Ouest 2,CH-1196 Gland, Switzerland.
↵||To whom correspondence should be addressed. E-mail: withers@chem.ubc.ca
↵* 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.
http://www.sciencemag.org/content/early/2013/02/20/science.1232552
Science DOI: 10.1126/science.1232552
Report
Mechanism-Based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity
Jin-Hyo Kim1,*,?,
Ricardo Resende1,*,
Tom Wennekes1,*,?,
Hong-Ming Chen1,*,
Nicole Bance2,
Sabrina Buchini1,?,
Andrew G. Watts3,
Pat Pilling4,
Victor A. Streltsov4,
Martin Petric5,
Richard Liggins6,
Susan Barrett4,
Jennifer L. McKimm-Breschkin4,
Masahiro Niikura2,
Stephen G. Withers1,||
+ Author Affiliations
1Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, B.C., V6T1Z1, Canada.
2Faculty of Health Sciences, Simon Fraser University, 8888 University Drive, Burnaby, B.C., V5A1S6, Canada.
3Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA27AY, UK.
4CSIRO Materials Science and Engineering, 343 Royal Pde, Parkville, 3052, Australia.
5British Columbia Centre for Disease Control, Provincial Health Services Authority, Vancouver, BC, V5Z 4R4, Canada.
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 Cit?-Ouest 2,CH-1196 Gland, Switzerland.
↵||To whom correspondence should be addressed. E-mail: withers@chem.ubc.ca
↵* 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.
http://www.sciencemag.org/content/early/2013/02/20/science.1232552