title: Mechanism-based covalent neuraminidase inhibitors with broad-spectrum influenza antiviral activity.
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 on a new class of specific, mechanism-based anti-influenza drugs that function through the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme, and we confirm this mode of action with 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.
authors: Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
authors: Jin-Hyo
authors: JH
authors: Kim
authors: Ricardo
authors: R
authors: Resende
authors: Tom
authors: T
authors: Wennekes
authors: Hong-Ming
authors: HM
authors: Chen
authors: Nicole
authors: N
authors: Bance
authors: Sabrina
authors: S
authors: Buchini
authors: Andrew G
authors: AG
authors: Watts
authors: Pat
authors: P
authors: Pilling
authors: Victor A
authors: VA
authors: Streltsov
authors: Martin
authors: M
authors: Petric
authors: Richard
authors: R
authors: Liggins
authors: Susan
authors: S
authors: Barrett
authors: Jennifer L
authors: JL
authors: McKimm-Breschkin
authors: Masahiro
authors: M
authors: Niikura
authors: Stephen G
authors: SG
authors: Withers
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D009439:Neuraminidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009975:Orthomyxoviridae / Q000187:drug effects* / Q000201:enzymology; D053139:Oseltamivir / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012794:Sialic Acids / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D053243:Zanamivir / Q000737:chemistry / Q000494:pharmacology
chemical_list: C579790:2,3-difluorosialic acid; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D012794:Sialic Acids; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir