한빛사 논문
Abstract
Seok-Joon Kwon1†, Dong Hee Na2†, Jong Hwan Kwak3†, Marc Douaisi1, Fuming Zhang1, Eun Ji Park2, Jong-Hwan Park4,5, Hana Youn6, Chang-Seon Song6, Ravi S. Kane1, Jonathan S. Dordick1, Kyung Bok Lee5* and Robert J. Linhardt1,7*
1Department 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. 2College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 702-701, Republic of Korea. 3School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. 4Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. 5Department of Biochemistry, College of Medicine, Konyang University, Daejeon 302-718, Republic of Korea. 6College of Veterinary Medicine, Konkuk University, Seoul 143-701, Republic of Korea. 7Department of Chemistry and Chemical Biology, Rensselaer Polytechnic Institute, Biotech 4005, 110 8th St., Troy, New York 12180, USA;
†These authors contributed equally to this work.
Correspondence to : Robert J. Linhardt or Kyung Bok Lee
Rapid change1 and zoonotic transmission to humans2 have enhanced the virulence of the influenza A virus (IAV)3. Neutralizing antibodies fail to provide lasting protection from seasonal epidemics1, 4. Furthermore, the effectiveness of anti-influenza neuraminidase inhibitors has declined because of drug resistance5. 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 m 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.
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