Strategies of Development of Antiviral Agents Directed Against Influenza Virus Replication

Abstract

In this review, we will discuss drug design based on proven and potential anti-influenza drug targets including viral hemagglutinin (HA), neuraminidase (NA), M2 ion channel, 3P polymerase complex, and host factors such as kinases. We have summarized influenza inhibitors based on their mode of actions. For instance, included are descriptions of (1) inhibitors of HA cleavage, such as nafamostat, camostat, gabexate, epsilon-aminocapronic acid and aprotinin, (2) inhibitors of fusion and entry, such as benzoquinones and hydroquinones, CL 385319, BMY-27709, stachyflin, and their analogues, (3) inhibitors of viral RNPs/polymerase/endonuclease, such as T-705, L-735,822, flutimide and their analogues, (4) inhibitors of MEK, such as PD 0325901, CI-1040 and ARRY-142886, and (5) inhibitors of NA such as DANA, FANA, zanamivir, and oseltamivir, etc. Although amantadine and rimantadine are not recommended for treating influenza virus infections because of drug resistance problem, these viral M2 ion channel blockers established a proof-of-concept that the endocytosis of virion into host cells can be a valid drug target because M2 protein is involved in the endocytosis process. The influenza polymerase complex not only catalyzes RNA polymerization but also encodes the "cap snatching" activity. After being exported from the nucleus to the cytoplasm, the newly synthesized vRNPs are assembled into virions at the plasma membrane. The progeny virions will then leave the host cells through the action of NA. The strategies for discovery of small molecule inhibitors of influenza virus replication based on each particular mechanism will be discussed. Finally, the lessons learned from the design of NA inhibitors (NAI) are also included. Many exciting opportunities await the cadre of virologists, medicinal chemists, and pharmacologists to design novel influenza drugs with favorable pharmacological and pharmacokinetic properties to combat this threatening infectious disease.

Identification of BPR3P0128 as an Inhibitor of Cap-Snatching Activities of Influenza Virus

“…The polymerase complex of the influenza virus is a potential target for the development of antiviral agents because it is responsible for an essential and highly conserved catalytic function of the virus and because the atomic and quasiatomic structures of its subunit have become available for antiviral drug design (9,28,49). The viral polymerase of influenza virus catalyzes the reactions responsible for both capped RNA-primed mRNA transcription (vRNA ¡ mRNA) and unprimed replication of vRNAs in the steps vRNA ¡ cRNA ¡ vRNA.…”

Closing the door on flaviviruses: Entry as a target for antiviral drug design

“…These studies have invited an alternative focus from inhibition of RNA replication towards blocking structural transitions required for efficient virus spread. Similar strategies were previously employed for antiviral design against the rhinoviruses (Badger et al, 1988;Hadfield, Diana, and Rossmann, 1999;Heinz et al, 1989;Rossmann, 1994;Rossmann et al, 2000) and enteroviruses (Padalko et al, 2004;Rossmann et al, 2000), and have recently gained momentum in other fields such as HIV (Copland, 2006;Veiga, Santos, and Castanho, 2006;Wang and Duan, 2007) and influenza (Hsieh and Hsu, 2007).…”

“…The active fusion core of viruses such as influenza and the human immunodeficiency virus constitutes a 6-helix bundle consisting of two helices from each fusion protein in the trimer (Skehel and Wiley, 2000;Melikyan et al, 2000;Russel et al, 2001;Chang et al, 2008). Its formation can be prevented by antiviral peptides that mimic the helices and compete with the protein-protein interactions that give rise to the fusion core (Hsieh and Hsu JT., 2007;Stevens and Donis, 2007).…”

Synthetic sialic-acid-containing polyvalent antiviral inhibitors

“…This represents a big disadvantage, considering the various mutations of the virus, which contribute to its preservation and thus become resistant to vaccines. A significant work has been developed in order to obtain anti-influenza drugs (Varghese, 1999;Matrosovich and Klenk, 2003;Hsieh and Hsu, 2007;Lagoja and De Clercq, 2008). Four pathways have been proposed for designing influenza virus inhibitors: M2 proton channel inhibitors; compounds resistant to NA influenza virus; compounds resistant to HA influenza virus; compounds resistant to both NA and HA.…”