From Neuraminidase Inhibitors to Conjugates: A Step Towards Better Anti-Influenza Drugs?

Abstract

For the treatment of seasonal flu and possible pandemic infections the development of new anti-influenza drugs that have good bioavailability against a broad spectrum of influenza viruses including the resistant strains is needed. In this review, we summarize previous methods for the structural modification of zanamivir, a potent neuraminidase inhibitor that has rare drug resistance, in order to develop effective anti-influenza drugs. We also report recent research into the design of multivalent zanamivir drugs and bifunctional zanamivir conjugates, some of which have shown better efficacy in animal experiments. As a step towards developing improved antivirals, conjugating anti-influenza drugs with anti-inflammatory agents can improve oral bioavailability and also exert synergistic effect in influenza therapy.

A new role of neuraminidase (NA) in the influenza virus life cycle: implication for developing NA inhibitors with novel mechanism of action

“…These residues are highly conserved in all NA subtypes . Based on the conserved catalytic site, intensive research has focused on structural modification of existing NAIs, as well as the design of novel NAIs, some of which have been previously reviewed . For example, new derivatives of oseltamivir were prepared by modifying the amino group with glycyl, acetyl, benzyl, and prolyl moieties in order to develop novel influenza virus inhibitors .…”

The PA Endonuclease Inhibitor RO-7 Protects Mice from Lethal Challenge with Influenza A or B Viruses

“…Despite the successful entry of these two endonuclease inhibitors into clinical trials, their structure and other preclinical data have not been disclosed. The development and refinement of the NAI class of antivirals (including the identification of NAI variants with enhanced activity, increased NA protein binding, and better bioavailability, and the development of multivalent analogues and NAIs conjugated to photodynamic and anti-inflammatory compounds) continues, despite the clinical availability of these drugs for two decades (57,58). Similarly, it is important to continue the study of other PA endonuclease inhibitors, including RO-7, with a view to future clinical trials.…”

Development of Influenza Virus Sialidase Inhibitors

“…These include modification of zanamivir through formation of "functional" prodrugs, and the use of perme ability enhancers [138]. Prodrug approaches for zanamvir (reviewed in [139]) include formation of an ester at the carboxylic acid that also neutralizes the charge on the guanidinium group through ion-pairing (18) [140], and amino acid-conjugated acyloxy ester prodrugs (19) at the carboxylic acid and/or on the glycerol side chain to take advantage of a carrier-mediated transport pathway in intestinal epithelial cells [141].…”

“…Considering this, it was envisaged that a multivalent presentation of zanamivir, with appropriate length and character of the linker, could block multiple active sites across a tetramer, and/or across tetramers on the one or different virus particles, leading to a gain in antiviral efficacy. Extension from the interaction-free C7 hydroxyl group has been used to develop such multivalent displays of zanamivir (reviewed in [48,139]). Di- [143] to tetra-valent zanamivir conjugates [148,149], as well as polymer-supported multivalent conjugates [150,151], have been constructed through C7-O-alkylation [150] or via a carbamate linker.…”

“…Further drug development programs focused on the development of inhibitors with similar high potency but with improved oral bioavailability, in particular through increased lipophilic character. An overview of the approaches taken to lead dis covery for the sialidase inhibitor anti-influenza drugs oseltamivir and peramivir is given in the following sections (and is reviewed in [74,75,77,139]). …”