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 M) 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.

l -Serine–modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier

“…The peaks corresponding to Ser were observed in the 1 H NMR spectrum at δ 3.72-3.85 (m, 2H) of Ser-PAMAM, and the integral ratio of the methylene protons of Ser to the methylene protons (CONHCH 2 ) of PAMAM (G3) indicates that the desired product was obtained (SI Appendix, Fig. S1B) (26).…”

Human Milk Oligosaccharides: Health Benefits, Potential Applications in Infant Formulas, and Pharmacology

“…It has been concluded that HMO at or below the level found in breast milk increases innate immunity to respiratory viruses in vitro and can affect innate immunity. As a result of blocking hemagglutination of influenza viruses, immobilized 3 SL and 6 SL attachments prevent infectivity of influenza viruses [60,61]. A number of external HMO connections have been identified that bind to influenza virus [60,61].…”

“…As a result of blocking hemagglutination of influenza viruses, immobilized 3 SL and 6 SL attachments prevent infectivity of influenza viruses [60,61]. A number of external HMO connections have been identified that bind to influenza virus [60,61]. A number of additional sialic acids containing HMO that bind to influenza virus have also been identified.…”

Designer DNA architecture offers precise and multivalent spatial pattern-recognition for viral sensing and inhibition

“…[7][8][9] Existing weakly binding ligands (called "binders" herein) that interact with these epitopes can be linked to a scaffold, but exhibit limited improvement on multivalent binding avidity when sporadically matching the average spacing of epitopes. [10][11][12][13][14] Herein, we demonstrate a unique strategy for potent viral detection and inhibition through a precise, spatial pattern-recognizing display of weak binders in two-dimensional (2D) space. This approach is particularly important for targeting disease-causing pathogens with complex patterns of surface antigens such as dengue virus (DENV).…”