ABSTRACT
Rapidly evolving influenza A viruses (IAVs) and influenza B viruses (IBVs) are major causes of recurrent lower respiratory tract infections. Current influenza vaccines elicit antibodies predominantly to the highly variable head region of haemagglutinin and their effectiveness is limited by viral drift1 and suboptimal immune responses2. Here we describe a neuraminidase-targeting monoclonal antibody, FNI9, that potently inhibits the enzymatic activity of all group 1 and group 2 IAVs, as well as Victoria/2/87-like, Yamagata/16/88-like and ancestral IBVs. FNI9 broadly neutralizes seasonal IAVs and IBVs, including the immune-evading H3N2 strains bearing an N-glycan at position 245, and shows synergistic activity when combined with anti-haemagglutinin stem-directed antibodies. Structural analysis reveals that D107 in the FNI9 heavy chain complementarity-determinant region 3 mimics the interaction of the sialic acid carboxyl group with the three highly conserved arginine residues (R118, R292 and R371) of the neuraminidase catalytic site. FNI9 demonstrates potent prophylactic activity against lethal IAV and IBV infections in mice. The unprecedented breadth and potency of the FNI9 monoclonal antibody supports its development for the prevention of influenza illness by seasonal and pandemic viruses.
Subject(s)
Antibodies, Viral , Antibody Specificity , Influenza A virus , Influenza B virus , Influenza Vaccines , Influenza, Human , Molecular Mimicry , Neuraminidase , Animals , Humans , Mice , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/chemistry , Antibodies, Viral/immunology , Antibodies, Viral/therapeutic use , Antibody Specificity/immunology , Arginine/chemistry , Catalytic Domain , Hemagglutinins, Viral/immunology , Influenza A virus/classification , Influenza A virus/enzymology , Influenza A virus/immunology , Influenza A Virus, H3N2 Subtype/enzymology , Influenza A Virus, H3N2 Subtype/immunology , Influenza B virus/classification , Influenza B virus/enzymology , Influenza B virus/immunology , Influenza Vaccines/chemistry , Influenza Vaccines/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/immunology , Influenza, Human/prevention & control , Neuraminidase/antagonists & inhibitors , Neuraminidase/chemistry , Neuraminidase/immunology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/prevention & control , Seasons , Sialic Acids/chemistryABSTRACT
A Cu2(OBA)2(BPY) metal-organic framework was utilized as a productive heterogeneous catalyst for the synthesis of 3-aroylquinolines via one-pot domino reactions of 2-aminobenzylalcohols with propiophenones. This Cu-MOF was considerably more active towards the one-pot domino reaction than a series of transition metal salts, as well as nano oxide and MOF-based catalysts. The MOF-based catalyst was reusable without a significant decline in catalytic efficiency. To the best of our knowledge, the transformation of 2-aminobenzylalcohols to 3-aroylquinolines was not previously reported in the literature, and this protocol would be complementary to previous strategies for the synthesis of these valuable heterocycles.