title: Nanostructured glycan architecture is important in the inhibition of influenza A virus infection.
abstract: Rapid change and zoonotic transmission to humans have enhanced the virulence of the influenza A virus (IAV). Neutralizing antibodies fail to provide lasting protection from seasonal epidemics. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance. Drugs that can block viral attachment and cell entry independent of antigenic evolution or drug resistance might address these problems. We show that multivalent 6'-sialyllactose-polyamidoamine (6SL-PAMAM) conjugates, when designed to have well-defined ligand valencies and spacings, can effectively inhibit IAV infection. Generation 4 (G4) 6SL-PAMAM conjugates with a spacing of around 3 nm between 6SL ligands (S3-G4) showed the strongest binding to a hemagglutinin trimer (dissociation constant of 1.6 × 10-7M) and afforded the best inhibition of H1N1 infection. S3-G4 conjugates were resistant to hydrolysis by H1N1 neuraminidase. These conjugates protected 75% of mice from a lethal challenge with H1N1 and prevented weight loss in infected animals. The structure-based design of multivalent nanomaterials, involving modulation of nanoscale backbone structures and number and spacing between ligands, resulted in optimal inhibition of IAV infection. This approach may be broadly applicable for designing effective and enduring therapeutic protection against human or avian influenza viruses.
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Seok-Joon
authors: 0000-0002-5466-1993
authors: SJ
authors: Kwon
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors: Dong Hee
authors: DH
authors: Na
authors: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors: Jong Hwan
authors: JH
authors: Kwak
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Marc
authors: M
authors: Douaisi
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Fuming
authors: F
authors: Zhang
authors: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea.
authors: Eun Ji
authors: EJ
authors: Park
authors: Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.|Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302-718, Republic of Korea.
authors: Jong-Hwan
authors: JH
authors: Park
authors: College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors: Hana
authors: H
authors: Youn
authors: College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea.
authors: Chang-Seon
authors: CS
authors: Song
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Ravi S
authors: RS
authors: Kane
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Jonathan S
authors: JS
authors: Dordick
authors: Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302-718, Republic of Korea.
authors: Kyung Bok
authors: KB
authors: Lee
authors: Department of Chemical and Biological Engineering and Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.|Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA.
authors: Robert J
authors: RJ
authors: Linhardt
mesh_terms: D000818:Animals; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D049329:Nanostructures / Q000737:chemistry / Q000627:therapeutic use; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011134:Polysaccharides / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D011134:Polysaccharides