Unsaturated N-acetyl- D-glucosaminuronic acid glycosides as inhibitors of influenza virus sialidase

Abstract

The threat of pandemic influenza is a significant concern of governments worldwide. There is a very limited and relatively expensive armament to tackle such a pandemic should it occur. This fact provides much impetus to the scientific community for the discovery of new and less expensive anti-influenza drugs. Our longstanding interest in the inhibition of influenza virus sialidase, coupled with the development of simple carbohydrates that mimic an unsaturated derivative of the enzyme's naturally-occurring ligand, N-acetylneuraminic acid, has led us to investigate the development of influenza virus sialidase inhibitors based on these mimetics. We have successfully prepared a range of these compounds, in good yield, from the relatively inexpensive carbohydrate N-acetylglucosamine utilising a short synthetic procedure. We have employed a sialidase inhibition assay for biological evaluation of the target compounds and to our delight these mimetics have displayed significant inhibition of influenza virus sialidase.

Antiviral Activity ofAspalathus linearisagainst Human Influenza Virus

“…However, since anti-influenza virus activity could only be observed in ethanol and alkaline extracts (Figure 1), the phenolic content present in the alkaline extract could represent a promising candidate for the active compound [5c, 9a-c]. In addition, Nakano et al mentioned that the alkaline extract of A. linearis contains uronic acid, which was also reported by Mann et al, which is effective in inhibiting influenza sialidase [7,13]. Our present results suggested that the alkaline extract of A. linearis, extracted using the same method as that described by Nakano et al [7], has potent inhibitory effects against the influenza virus at late stages of infection.…”

A Simple Synthetic Access to Differently 4‐Substituted Neu5Ac2en Glycals Combining Elements of Molecules with Anti‐Neuraminidase Activity

“…Various glycals of N-acetylated neuraminic acid 1 (Neu5Ac; Figure 1), such as, for example, 5-acetamido-2,6anhydro-3,5-dideoxy-d-glycero-d-galacto-non-2-enoic acid 2a (Neu5Ac2en, DANA), [1][2][3][4][5] its 5-perfluoroacetylated analogue 2b (FANA), [6] and the 4-deoxy-4-guanidino congeners of DANA (i.e., Zanamivir, 2c) [1][2][3]7] and of FANA (i.e., 2d), [8] are potent inhibitors of sialidases (neuraminidases, NA). Sialidases are important surface glycoproteins of bacterial and viral membranes that play crucial roles in the spreading of infection to new host cells.…”

Exploring the Interactions of Unsaturated Glucuronides with Influenza Virus Sialidase

“…4,5 Importantly, presumably by virtue of the hydrophobic side-chain binding subsite 2, 4 retains potent inhibition against influenza A viruses harboring the E119 V mutation that confers resistance to OC 2. 10 We are interested in the development of readily accessible uronic acid-based sialidase inhibitors of type 7 (Figure 2), 11,12 2-acetamido-2-deoxy-Δ 4 -β-D-glucuronides which mimic the naturally occurring sialidase inhibitor 5-acetamido-2,6-anhydro-3,5-dideoxy-D-glycero-D-galacto-non-2-enonic acid (Neu5A-c2en 8) but in which the glycerol side-chain of 8 is replaced by an ether (the glycoside of the glucuronide). An advantage of the uronic acid scaffold is its derivation from inexpensive 2-acetamido-2-deoxy-glucose (GlcNAc) compared to N-acetylneuraminic acid and quinic acid used for the syntheses of 1 and 2, respectively.…”

“…Conversion of glucuronide 14 to the 4,5-unsaturated derivative, Δ 4 -β-D-glucuronide 16, was achieved through DBU-mediated β-elimination. 11,12 To obtain the 3-hydroxy glucuronide 17 for further functionalization at C3, chemoselective cleavage of the C3 O-acetate in the presence of the methyl ester was undertaken using sodium methoxide in methanol. The overall yield of key intermediate 17 in 8 steps from GlcNAc 10 was 40%.…”