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In the initial stages of influenza virus infection, the hemagglutinin (HA) protein of influenza virus mediates both adsorption and penetration of the virus into the host cell. Recently, we identified and characterized BMY-27709 as an inhibitor of the H1 and H2 subtypes of influenza A virus that specifically inhibits the HA function necessary for virus-cell membrane fusion (G.-X. Luo, R. Colonno, and M. Krystal, Virology 226:66-76, 1996). Studies presented herein show that the inhibition is mediated through specific interaction with the HA protein. This binding represses the low-pH-induced conformational change of the HA protein which is a prerequisite for membrane fusion. In an attempt to define the binding pocket within the HA molecule, a number of drug-resistant viruses have been isolated and characterized. Sequence analyses of the HA gene of these drug-resistant viruses mapped amino acid changes responsible for drug resistance to a region located near the amino terminus of HA2. In addition, we have identified inactive analogs of BMY-27709 which are able to compete out the inhibitory activity of BMY-27709. This finding suggests that inhibition of the HA-mediated membrane fusion by this class of compounds is not solely the result of binding within the HA molecule but requires specific interactions.

Condensation of 1,6-N,O-carbonyl-3-N-ethoxycarbonyl-2,5-dideoxystreptamine (7) with 6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl chloride by the Koenigs–Knorr reaction produced the α-glycoside 10. The cyclic carbamate of 10 was opened with ethanol in the presence of sodium ethoxide and the resulting 4-O-(6-azido-2,3,4-tri-O-benzyl-6-deoxy-α-D-glucopyranosyl)-N,N′-diethoxycarbonyl-2,5-dideoxystreptamiue (12) was glycosidated with 3-acetamido-2,4,6-tri-O-benzyl-3-deoxy-α-D-glucopyranosyl chloride (21) to give the α,α-diglycoside 22. Hydrogenation of the azido group and removal of the protective groups gave 5-deoxykanamycin A (25), an antibiotic with a potency about half that of kanamycin A.

The preparation of (4-tritylthio-2-azetidinon-l-yl)triphenylphosphoranylideneacetates from 4-acetoxyazetidin-2-one is described. They are easily converted to mercuric or silver mercaptides. These mercaptides are acylated with a wide variety of acylating agents and cyclized to 2-substituted penem-3-carboxylates.