New small-molecule drug design strategies for fighting resistant influenza A

Abstract

Influenza A virus is the major cause of seasonal or pandemic flu worldwide. Two main treatment strategies-vaccination and small molecule anti-influenza drugs are currently available. As an effective vaccine usually takes at least 6 months to develop, anti-influenza small molecule drugs are more effective for the first line of protection against the virus during an epidemic outbreak, especially in the early stage. Two major classes of anti-influenza drugs currently available are admantane-based M2 protein blockers (amantadine and rimantadine) and neuraminidase (NA) inhibitors (oseltamivir, zanamivir, and peramivir). However, the continuous evolvement of influenza A virus and the rapid emergence of resistance to current drugs, particularly to amantadine, rimantadine, and oseltamivir, have raised an urgent need for developing new anti-influenza drugs against resistant forms of influenza A virus. In this review, we first give a brief introduction of the molecular mechanisms behind resistance, and then discuss new strategies in small-molecule drug development to overcome influenza A virus resistance targeting mutant M2 proteins and neuraminidases, and other viral proteins not associated with current drugs.

Keywords: Drug discovery; Influenza A virus; M2 ion channel; Neuraminidase; Resistance.

Graphical abstract

Figure 1

A schematic presentation of influenza A virus life cycle (adapted with permission from Ref. life cycle Copyright 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim).

Figure 2

Structures of M2 ion channel blockers.

Figure 3

Residues around the SA active site of NA (N1) with oseltamivir and the relative positions of 150 and 430 loop of N1 versus N9 (N1: light blue, PDB 2HU0, N9: yellow, PDB 2C4A) (adapted with permission from Ref. , Copyright 2012 Elsevier Ltd.).

Figure 4

Sialic acid and neuraminidase (NA) inhibitors.

Figure 5

Anti-influenza drugs targeting other viral proteins besides M2 ion channel and NA.