Synthetic sialic-acid-containing polyvalent antiviral inhibitors

Abstract

This review gives a brief survey of synthetic inhibitors of influenza virus which have been synthesized to date. It starts with a short introduction which describes the structure and mechanism of action of influenza virus and continues with the main research directions that have been used in order to inhibit the virus. This is followed by discussion of various synthetic materials, including synthesis and antiviral properties, which that have been tested against influenza virus. The most potent inhibitory compounds proved to be polyvalent, because of their high binding affinity and steric stabilization. Finally we conclude with a brief discussion on structural characteristics, a summary, and outlook overview.

Conjugating drug candidates to polymeric chains does not necessarily enhance anti‐influenza activity

“…In previous studies of the effect of multivalency on anti-influenza inhibitors, the receptor of the multivalent ligand was proximal to the solvent-exposed outer edge of the surface protein. 2,4,[6][7][8][9][10][11] Although the exact location of binding of 1 and its analogs to hemagglutinins in the strains studied herein is unknown, our docking studies (Fig. 4) predict that for 10 and 16 the site is located approximately half-way down the protein for the X-31 strain and close to the viral envelope for the linker-attached inhibitor (16) on the Puerto Rico strain.…”

“…This compound, which differs from 1 only by a methyl substituent in the benzoquinone portion of the molecule, exhibited an IC 50 value comparable to that of 1; converting it to 12 produced a 52-fold jump in inhibitory activity (Table 1). Interestingly, however, in the case of 10 attached to the polymer with no spacer arm (11), no increase (and, in fact, a sizeable decline) in the potency was observed (Table 1), illustrating how subtle the SAR is.…”

“…In light of the previous studies with polymer-attached Zanamivir and sialic acid, 2,4,[6][7][8][9][10][11] we next tested whether covalent conjugation of multiple copies of 1 to a polymeric chain would increase anti-influenza potency. To this end, 1 was attached to the physiologically benign and biodegradable polymer poly-L-glutamate at a ~10% loading (i.e., with approximately one tenth of all monomeric units being derivatized with the inhibitor).…”

“…2,4,[6][7][8][9][10][11] Conjugating multiple copies of influenza inhibitors to a flexible polymeric chain has been shown to result in multivalent interactions between the polymerattached inhibitors and the viral surface receptor proteins. 2,4,[6][7][8][9][10][11] These enhanced interactions, in turn, lead to a much stronger binding compared to that of the small-molecule parents stemming from favorable entropic factors; additionally, water-swollen polymeric chains may sterically hinder physical contacts between the virus and the target cell. 6 The foregoing benefits of multivalency for binding to influenza virus have been demonstrated for viral surface proteins with the natural ligand of hemagglutinin, Nacetylneuraminic (sialic) acid, and with the neuraminidase inhibitor Zanamivir.…”

“…6 The foregoing benefits of multivalency for binding to influenza virus have been demonstrated for viral surface proteins with the natural ligand of hemagglutinin, Nacetylneuraminic (sialic) acid, and with the neuraminidase inhibitor Zanamivir. 2,4,[6][7][8][9][10][11] However, both of these compounds are structurally complex requiring many-step syntheses to become amenable to attachment to polymeric chains in order to investigate the effect of multivalency. 2,4 They are also difficult to modify selectively and thus not optimal for structure-activity relationship (SAR) studies.…”