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  • Title: A strategy for neuraminidase inhibitors using mechanism-based labeling information.
    Author: Hinou H, Miyoshi R, Takasu Y, Kai H, Kurogochi M, Arioka S, Gao XD, Miura N, Fujitani N, Omoto S, Yoshinaga T, Fujiwara T, Noshi T, Togame H, Takemoto H, Nishimura S.
    Journal: Chem Asian J; 2011 Apr 04; 6(4):1048-56. PubMed ID: 21305698.
    Abstract:
    A potent inhibitor for Vibrio cholerae neuraminidase (VCNA) was developed by using a novel two-step strategy, a target amino acid validation using mechanism-based labeling information, and a potent inhibitor search using a focused library. The labeling information suggested the hidden dynamics of a loop structure of VCNA, which can be a potential target of the novel inhibitor. A focused library composed of 187 compounds was prepared from a 9-azide derivative of 2,3-dehydro-N-acetylneuraminic acid (DANA) to interrupt the function of the loop of the labeled residues. Inhibitor 3 c showed potent inhibition properties and was the strongest inhibitor with FANA, a N-trifluoroacetyl derivative of DANA. Validation studies of the inhibitor with a detergent and a Lineweaver-Burk plot suggested that the 9-substitution group would interact hydrophobically with the target loop moiety, adding a noncompetitive inhibition property to the DANA skeleton. This information enabled us to design compound 4 having the combined structure of 3 c and FANA. Compound 4 showed the most potent inhibition (K(i) =73 nM, mixed inhibition) of VCNA with high selectivity among the tested viral, bacterial, and mammal neuraminidases.
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