J Bacteriol Virol.  2012 Jun;42(2):108-120. 10.4167/jbv.2012.42.2.108.

Potential Therapeutics Against Flaviviruses

• Lim PO
• Lee TH
• Chung KM

• KMID: 1717682
• DOI: http://doi.org/10.4167/jbv.2012.42.2.108

Abstract

Flaviviruses have been important human pathogens after emerging and resurging flavivirus diseases over the past decades. Although effective therapeutic agents are not yet commercially available for use in humans, significant progress has been made toward developing effective therapeutics and treatments. Several studies have shown that antibodies against the flaviviral E and NS1 proteins play a central role in prophylaxis and/or treatment of flavivirus infection through passive immunization. In addition, many anti-flavivirals, including interferons, oligonucleotide-based platforms, and small compounds, have been developed and evaluated for their antiviral effects. This review provides an overview of various approaches to the development of anti-flaviviral candidates and new insights that could improve our strategies for designing effective therapeutics against flaviviruses.

Keyword

Flaviviruses; Therapeutics; Antibody; Anti-flavivirals

MeSH Terms

Antibodies
Flavivirus
Flavivirus Infections
Humans
Immunization, Passive
Interferons
Proteins
Antibodies
Interferons
Proteins

Figure

• 

  Figure 1 Schematic of flavivirus E and its antibody. The structure of the dimer of flavivirus E protein is schematically represented. "I", "II", and "III" represent Domain I, Domain II, and Domain III, respectively. Domain I and II participate in the pH-dependent fusion of virus-host cells, and Domain III has been suggested as a host receptor binding site. Although most neutralizing monoclonal antibodies (mAbs) recognize Domain III, broadly cross-neutralizing flavivirus mAbs primarily react with Domain II.

• 

  Figure 2 Protection model of neutralizing antibody. (A) Blockage of virion attachment and entry. Neutralizing antibodies that are directed against the E protein inhibit virion attachment and entry by blocking receptor engagement or membrane fusion. (B) Inhibition of virion uncoating. Some neutralizing antibodies interfere with fusion of the virion and endosomal membrane, which results in lysosomal destruction of the virion.

• 

  Figure 3 Protection model of non-neutralizing antibody through immune mechanisms. (A) Complement-mediated cytolysis of infected cells. Antibodies bound to a specific antigen on flavivirus-infected cells interact with C1q complement factor, which leads to activation of the classical complement pathway and eventually induces membrane attack complex (MAC)-mediated lysis of virus-infected cells. (B) Antibody-mediated complement lysis of virions. The antiviral effects of some neutralizing antibodies are efficiently enhanced by inducing lysis of the virion through antibody-mediated complement activation, which leads to fragmentation of the viral envelope. (C) and (D) Antibody-dependent clearance of viral particles and infected cells through Fc-γ receptor(s). Antibody binding to viral particles and infected cells recruits immune-effect cells such as macrophages, which interact with the Fc region of the antibody through the Fc-γ receptor expressed by the effect cells. The antibody-bound virions and infected cells are then phagocytosed by the immune cells.

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