Chemical probes for drug-resistance assessment by binding competition (RABC): oseltamivir susceptibility evaluation.

The wizard of OS (resistance): the binding difference of neuraminidase inhibitors (zanamivir versus oseltamivir (OS)) was used to establish an assay to identify the influenza subtypes that are resistant to OS but still sensitive to zanamivir. This assay used a zanamivir-biotin conjugate to determine the OS susceptibility of a wide range of influenza viruses and over 200 clinical isolates.

A practical synthesis of zanamivir phosphonate congeners with potent anti-influenza activity.

Two phosphonate compounds 1a (4-amino-1-phosphono-DANA) and 1b (phosphono-zanamivir) are synthesized and shown more potent than zanamivir against the neuraminidases of avian and human influenza viruses, including the oseltamivir-resistant strains. For the first time, the practical synthesis of these phosphonate compounds is realized by conversion of sialic acid to peracetylated phosphono-DANA diethyl ester (5) as a key intermediate in three steps by a novel approach. In comparison with zanamivir, the high affinity of 1a and 1b can be partly attributable to the strong electrostatic interactions of their phosphonate groups with the three arginine residues (Arg118, Arg292, and Arg371) in the active site of neuraminidases. These phosphonates are nontoxic to the human 293T cells; they protect cells from influenza virus infection with EC(50) values in low-nanomolar range, including the wild-type WSN (H1N1), the 2009 pandemic (H1N1), the oseltamivir-resistant H274Y (H1N1), RG14 (H5N1), and Udorn (H3N2) influenza strains.

Analogs of zanamivir with modified C4-substituents as the inhibitors against the group-1 neuraminidases of influenza viruses.

Unlike the group-2 neuraminidase, the group-1 neuraminidase of influenza virus possesses a flexible loop (the 150-loop) and a cavity (the 150-cavity) adjacent to the active site, and renders a conformational change from the 'open' form to the 'closed' form on binding with substrate (sialo-glycoprotein) or inhibitor (e.g., zanamivir). Zanamivir derivative 8a having an extended (piperazinocarbonyl)propyl substituent at the internal N-position of the guanidino group is designed as a possible inhibitor on the basis of computer docking to the open form of N1 subtype neuraminidase. Indeed, compound 8a exhibits strong neuraminidase inhibition and good anti-influenza activity against H1N1 virus with IC(50)=2.15microM and EC(50)=0.77microM, respectively. This study may provide a clue to future design of better group-1 neuraminidase inhibitors.

Synergistic effect of zanamivir-porphyrin conjugates on inhibition of neuraminidase and inactivation of influenza virus.

New anti-influenza agents of tetravalent zanamivir on a porphyrin scaffold were synthesized. These compounds are 10 to 100 times more potent in inhibiting influenza replications even though they are somewhat less potent in neuraminidase inhibition than the monomeric zanamivir. The enhanced anti-influenza activity is probably attributable to the additional viral inactivation by singlet oxygen due to sensitization of the porphyrin moiety, which is brought in close proximity of virus by the conjugated zanamivir in a manner resembling the "magic bullet" mechanism.

Two-stage sensing property via a conjugated donor-acceptor-donor constitution: application to the visual detection of mercuric ion.

A conjugated donor-acceptor-donor molecule incorporating a central moiety of naphthyridine and two terminal moieties of di(hydroxyethyl)aniline connected by ethynyl bridges shows two-stage color changes on binding with mercury(II) ion in Me(2)SO/H(2)O (1:1) solution with a bathochromic shift from 450 to 498 nm, and then an extraordinarily large hypsochromic shift to 378 nm. In comparison, the corresponding donor-acceptor molecule weakly binds mercury(II) ion with a hypsochromic shift from 408 to 375 nm. Our designed sensor of the donor-acceptor-donor system shows high selectivity toward mercury(II) ion over other competing metal ions.