The current state of research on influenza antiviral drug development: drugs in clinical trial and licensed drugs

Abstract

Influenza viruses (IVs) threaten global human health due to the high morbidity, infection, and mortality rates. Currently, the influenza drugs recommended by the FDA are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. Notably, owing to the high variability of IVs, no drug exists that can effectively treat all types and subtypes of IVs. Moreover, the current trend of drug resistance is likely to continue as the viral genome is constantly mutating. Therefore, there is an urgent need to develop drugs related to the treatment of influenza to deal with the next pandemic. Here, we summarized the cutting-edge research in mechanism of action, inhibitory activity, and clinical efficacy of drugs that have been approved and drugs that are still in clinical trials for influenza treatment. We hope this review will provide up-to-date and comprehensive information on influenza antivirals and generate hypotheses for screens and development of new broad-spectrum influenza drugs in the near future.

Keywords: adverse event; antiviral drugs; clinical drugs; influenza virus; mechanism of action.

Fig 1

Influenza virus (IV) infections life cycle and associated drug action stages. IVs contact sialic acid on host cells through surface HA and encapsulate virus particles in endosomes by endocytosis. In the low pH environment, H⁺ enters the virus through the M2 ion channel, and under the action of the fusion peptide, the viral membrane fuses with the endosome membrane, releasing the viral genome into the cytoplasm and then into the nucleus. The viral RNA is transcribed, copied, and translated by RNA polymerase. Finally, it is assembled on the surface of the cell membrane and hydrolyzes sialic acid with Na to help release the mature progeny virus.

Fig 2

Crystal structures of small molecule drugs of influenza virus. Binding sites of small molecules and related subunits are shown in the box. M2 protein and amantadine complex (PDB code: 3C9J), NA and zanamivir, oseltamivir, peramivir, laninamivir complex (PDB codes: 4MWR, 4MWW, 4MX0, and 4MWY), HA and arbidol, JNJ4796 complex (PDB codes: 5T6S and 6CFG), PB1 and favipiravir complex (PDB code: 4KN6), PA and baloxavir marboxil complex (PDB code: 6FS6), PB2 and pimodivir complex (PDB code: 7AS0). The crystal structures were obtained from the Protein Data Bank (PDB) and rendered using PyMol software.

Fig 3

Chemical structures of influenza virus small molecule drugs. The chemical structures of related small molecule drugs were drawn using ChemDraw software.

Fig 4

Crystal structures of antibodies against influenza virus glycoprotein. The HA monomers (gray and red) bind to the heavy (blue) and light (yellow) chains of the antibodies. 39.29 (PDB code: 4KVN), CR8020 (PDB code: 3SDY), CR6261 (PDB code: 3GBM), MEDI8852 (PDB code: 5JW4), and 1G01 (PDB code: 6Q23). Graphics acquisition and rendering methods are the same as Fig. 2.