Abstract
Virus entry into a susceptible host cell is the first step in the formation of all viral diseases. Controlling viral infections by disrupting viral entry is advantageous for antibody-mediated neutralization by the host’s immune system and as a preventive and therapeutic antiviral strategy. Recently, several plant-derived carbohydrate-binding proteins (lectins) have emerged as a new class of antiviral biologics by taking advantage of a unique glycosylation pattern only found on the surface of viruses. In particular, a red algae-derived griffithsin (GRFT) protein has demonstrated superior in vitro and in vivo antiviral activity with minimum host toxicity against a variety of clinically relevant, enveloped viruses. This review examines the structural characteristics of GRFT, focusing on its carbohydrate-binding capability. Its in vitro antiviral profiles against human immunodeficiency virus (HIV) are also discussed followed by a description of the results from a combination study using anti-HIV drugs. The results of several studies regarding its novel antiviral mechanism of action are provided in conjunction with an explanation of viral resistance profiles to GRFT. In addition, its in vitro and in vivo host toxicity profiles are summarized with its pharmacokinetic behavior using in vivo efficacy study results. Also, a large-scale production and formulation strategy, as well as a drug delivery strategy, for GRFT as a new class of broad-spectrum microbicides is discussed. Finally, results from two ongoing clinical studies examining GRFT’s effects on viruses are presented.
Highlights
Every virus starts its life cycle by entering a susceptible host cell
Asp112) play a critical carbohydrate-binding to be essential for its(Asp30, high-affinity potency at role in the interaction of GRFT with high-mannose type oligosaccharides such as Man9GlcNAc2, whichdrug is composed of nine mannose molecules and two N-acetyl glucosamines
To study the potential role of the GRFT dimer in the suppression of human immunodeficiency virus (HIV)-1 infectivity, either two or four amino acids were inserted at the dimerization interface of GRFT. This resulted in a monomeric form of GRFT with greatly reduced antiviral activity against HIV-1
Summary
Every virus starts its life cycle by entering a susceptible host cell. The host cell-targeting ability of a virus is mainly determined by the presence of appropriate host cell receptors which are engaged by a virus. Due to its essential role in the overall virus life cycle, viral entry has been an attractive target for both vaccine and antiviral drug development with the goal of disrupting the binding of viral glycoproteins to host cell receptors. Its antiviral activity relates to a unique structural feature that forms a homodimeric complex with three carbohydrate-binding domains on each monomer (Figure 2) These three carbohydrate-binding domains target high-mannose arrays present on many pathogenic enveloped viruses including HIV; severe, acute, or Middle East respiratory syndrome coronaviruses (SARS-CoV or MERS-CoV) [10,11]; hepatitis C virus (HCV) [12,13]; herpes simplex virus 2 (HSV-2) [14,15]; Japanese encephalitis virus (JEV) [16,17]; and porcine epidemic diarrhea virus (PEDV) [18].
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