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Review
. 2012 Oct;2(5):614-21.
doi: 10.1016/j.coviro.2012.09.003.

Virus-host interactomes--antiviral drug discovery

Yue Ma-Lauer  1 , Jian Lei, Rolf Hilgenfeld, Albrecht von Brunn
Affiliations
Review

Virus-host interactomes--antiviral drug discovery

Yue Ma-Lauer et al. Curr Opin Virol. 2012 Oct.

Abstract

One of the key questions in virology is how viruses, encoding relatively few genes, gain temporary or constant control over their hosts. To understand pathogenicity of a virus it is important to gain knowledge on the function of the individual viral proteins in the host cell, on their interactions with viral and cellular proteins and on the consequences of these interactions on cellular signaling pathways. A combination of transcriptomics, proteomics, high-throughput technologies and the bioinformatical analysis of the respective data help to elucidate specific cellular antiviral drug target candidates. In addition, viral and human interactome analyses indicate that different viruses target common, central human proteins for entering cellular signaling pathways and machineries which might constitute powerful broad-spectrum antiviral targets.

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Figures

Figure 1
Figure 1
Concept of studying virus–host interactions by large-scale high throughput methods. Y2H is used for initial screening of viral orfeomes (cloned virus ORFs) against human cDNA libraries expressing human genes. Positive protein interaction pairs are validated in mammalian cells by various methods including (modified) LUMIER, PCA, F2H, etc. Crystal structure analysis is performed on especially interesting protein interaction complexes. Bioinformatic analysis of cellular interaction partners of viral proteins aims at the identification of viral and cellular proteins and signaling pathways as targets for antiviral therapy.
Figure 2
Figure 2
Influence of CsA, FK506, and SARS-CoV Nsp1 on NFAT signaling (i) and viral replication (ii). (i) CsA and FK506 interact with PPIA and FKBP1A, respectively. The complex of CsA/PPIA or FK506/FKBP1A blocks the catalytic domain of calcineurin (Cn), thereby inhibiting dephosphorylation of NFATc transcription factors. Consequently, the phosphorylated NFATc cannot translocate into the nucleus to induce expression of cytokines [66, 67]. FKBP1A also interacts with the ryanodine receptor (RyR1) and the inositol trisphosphate receptor (IP3R), which are calcium channels at the ER membrane [68, 69]. Adding FK506 results in calcium release from the ER. Decrease of the calcium concentration at the ER is then sensed by the stromal interaction molecule (STIM). Subsequently, STIM activates the Ca2+ release-activated Ca2+ channel (CRAC) via protein–protein interaction at the plasma membrane, resulting in Ca2+ influx from the extracellular space [70]. The Ca2+ influx is required for the activation of Cn through a calcium sensor calmodulin CaM. SARS-CoV Nsp1 binds to Cn (own observation, unpublished). Virus infection and Nsp1 overexpression induce NFAT activity in vitro, which is blocked in the presence of CsA and FK506. (ii) Nsp1 binds to PPIA and FKBP1A. CsA binding to PPIA or FK506 binding to FKBP1A inhibit coronaviral replication in cell culture, probably by interrupting the formation of PPIA/Nsp1 or FKBP1A/Nsp1 complexes.
Figure 3
Figure 3
Cartoon view of cyclophilin A (cyan) and HIV-1 capsid (yellow) complex structure (PDB ID: 1AK4) [49]. The binding site of CsA overlaps with the loop (red) connecting alpha helix 4 and the helical turn alpha 5 of CA, which binds to the active groove of cyclophilin.
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