Barrêre B, Driguez P A, Maudrin J, Doutheau A, Aymard M, Quash G
Laboratoire d'Immunochimie, Faculté de Médecine Lyon-Sud, Oullins, France, France.
Laboratoire de Chimie Organique, INSA, Villeurbanne, France, and, France.
Arch Virol. 1997 Jul;142(7):1365-1380. doi: 10.1007/s007050050166.
The sodium salts of 2-difluoromethyl-phenyl-α-ketoside of N-acetyl-neuraminic acid (compound 1) and of 4-difluoromethyl-2-methoxy-phenyl-α-ketoside of N-acetylneuraminic acid (compound 2) were designed as potential mechanism-based inhibitors of sialidase. In vitro both of these compounds competitively inhibited the sialidases of Clostridium perfringens and of influenza virus A/HK/1/68. Inhibition was irreversible with the sialidase of Clostridium perfringens whereas it was reversible with that of A/HK/1/68. Compound 2 did not inhibit the hemagglutinin of the virus but exhibited significant anti-influenza activity when added to the medium of Madin-Darby canine kidney (MDCK) cells infected by influenza virus. In non-infected MDCK cells no inhibition of cellular sialidase was observed. Compound 2 did not block primary infection, but inhibited the release of progeny virus from infected cells. Even after 8 passages in its presence, no resistant strains were detected. Because of its high Ki (8 × 10M) compared to the low Ki (1 × 1 M) of 4 guanidino-Neu 5 Ac 2en and its reversible inhibition of viral sialidase, its development as an anti-influenza agent is no longer envisaged. Nevertheless, as a mechanism-based irreversible inhibitor of the bacterial enzyme, it could at least be useful for investigating the intrinsic role of sialidase in infections caused by this strain.
N-乙酰神经氨酸的2-二氟甲基苯基-α-酮糖苷（化合物1）和N-乙酰神经氨酸的4-二氟甲基-2-甲氧基苯基-α-酮糖苷（化合物2）的钠盐被设计为潜在的基于机制的唾液酸酶抑制剂。在体外，这两种化合物都竞争性抑制产气荚膜梭菌和甲型流感病毒A/HK/1/68的唾液酸酶。对产气荚膜梭菌的唾液酸酶抑制作用是不可逆的，而对A/HK/1/68的唾液酸酶抑制作用是可逆的。化合物2不抑制病毒的血凝素，但添加到感染流感病毒的犬肾传代细胞（MDCK）培养基中时表现出显著的抗流感活性。在未感染的MDCK细胞中未观察到对细胞唾液酸酶的抑制作用。化合物2不阻断初次感染，但抑制子代病毒从感染细胞中释放。即使在其存在下传代8次后，也未检测到耐药菌株。由于与4-胍基-Neu5Ac2en的低Ki（1×10⁻¹¹M）相比其Ki较高（8×10⁻⁸M），且对病毒唾液酸酶的抑制作用是可逆的，因此不再设想将其开发为抗流感药物。然而，作为细菌酶的基于机制的不可逆抑制剂，它至少可用于研究唾液酸酶在该菌株引起的感染中的内在作用。
