Retracted and republished from: "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 Food and Drug Administration are oseltamivir, zanamivir, peramivir, and baloxavir marboxil. These recommended antivirals are currently effective for major subtypes of IVs as the compounds target conserved domains in neuraminidase or polymerase acidic (PA) protein. However, this trend may gradually change due to the selection of antiviral drugs and the natural evolution of IVs. 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

IV infections life cycle and associated drug action stages contain currently approved and unapproved drugs by the FDA, with approved drugs shown in orange font and others in green. IV contacts sialic acid on host cells through surface HA and encapsulates 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 neuraminidase (NA) to help release the mature progeny virus.

Fig 2

Crystal structures of small molecule drugs of IV. The 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 code: 4MWR, 4MWW, 4MX0 and 4MWY), HA and Arbidol, JNJ4796 complex (PDB code: 5T6S and 6CFG), PB1 and Favipiravir complex (PDB code: 4KN6), PA and Baloxavir marboxil complex (PDB code: 6FS6), and 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 IV small molecule drugs. The chemical structures of related small molecule drugs were drawn using Chemdraw software.

Fig 4

Crystal structures of antibodies against IV glycoprotein. The HA monomers (gray and red) bind to the heavy (blue) and light (yellow) chains of the antibodies. MHAA4549A (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.