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
- ↵||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.
- Received for publication 9 November 2012.
- Accepted for publication 13 February 2013.
No hay comentarios:
Publicar un comentario