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Guanidinoglycosides: A Novel Family of RNA Ligands.-The title compounds (I) and (II) are prepared by treatment of aminoglycosides with N,N-di-tert-butoxycarbonyl-N-triflylguanidine. They bind RNA preferentially over DNA and show selectivity between various RNAs. Their higher affinity and selectivity to the RRE implicate their potential use as antiviral agents. -

The new guanidinylation reagent N,N‘-diBoc-N‘ ‘-triflylguanidine was used to efficiently convert multiamine-containing glycosides including kanamycin A and B, tobramycin, paromomycin, and neomycin B to the corresponding fully guanidinylated analogues (guanidinoglycosides). This transformation occurs in the presence of H2O under mild conditions. Guanidinotobramycin and guanidinoneomycin B were found to inhibit the replication of the HIV virus with activities approximately 100 times greater than the parent aminoglycosides.

The absence of viral receptors is a major barrier to efficient gene transfer in many cells. To overcome this barrier, we developed an artificial receptor based on expression of a novel sugar. We fed cells an unnatural monosaccharide, a modified mannosamine that replaced the acetyl group with a levulinate group (ManLev). ManLev was metabolized and incorporated into cell-surface glycoconjugates. The synthetic sugar decorated the cell surface with a unique ketone group that served as a foundation on which we built an adenovirus receptor by covalently binding biotin hydrazide to the ketone. The artificial receptor enhanced adenoviral vector binding and gene transfer to cells that are relatively resistant to adenovirus infection. These data are the first to suggest the feasibility of a strategy that improves the efficiency of gene transfer by using the biosynthetic machinery of the cell to engineer novel sugars on the cell surface.In many cells, lack of appropriate cell surface receptors is a major barrier to efficient viral-mediated gene transfer. One strategy to overcome this barrier is to chemically or genetically engineer new ligands onto the virus so that it will bind to existing cell receptors (1-3). A hypothetical second strategy would be to engineer the cell surface to display new receptors for existing gene transfer vectors. The goal of this work was to explore this second strategy.N-Acetylneuraminic acid, a member of the sialic acid family, is the most abundant terminal sugar residue on mammalian cell glycoproteins and glycolipids (4). Biosynthesis of this sialic acid requires extensive enzymatic modification of N-acetylmannosamine before incorporation into the terminal position on oligosaccharides and expression on the cell surface (5, 6). The cellular enzymes responsible for synthesis of N-acetylneuraminic acid are known to tolerate substitutions at the N-acyl position of N-acetylmannosamine. When various N-acylmannosamines were present in the culture medium, modified sialic acids were incorporated into carbohydrates and expressed on the cell surface (7-9). Likewise, intraperitoneal injection of modified monosaccharides allowed expression of their metabolites on serum glycoproteins in rats (9). Bertozzi and co-workers (10) constructed a modified mannosamine that replaced the acetyl group with a levulinate group (named ManLev). They found that ManLev was metabolically incorporated into glycoconjugates and expressed on the surface of three cell lines. A unique feature of ManLev is that it places a ketone group on the cell surface. Because ketone groups are virtually absent from the surface of cells, metabolic incorporation of ManLev provides a novel functional group to which other molecules can be attached (10). In this study, we tested the hypothesis that ManLev could be used to create novel artificial viral receptors that would enhance adenovirus-mediated gene transfer in poorly infected cells. EXPERIMENTAL PROCEDURESCell Culture and Adenovirus Vector-NIH-3T3 were cultured on 8-well plastic slides (Nalge ...

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