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Review
. 2014 Nov 26;114(22):11382-412.
doi: 10.1021/cr500255e. Epub 2014 Oct 2.

Current and potential treatments for ubiquitous but neglected herpesvirus infections

Jonathan E Gable  1   2 , Timothy M Acker  1 , Charles S Craik  1
Affiliations
Review

Current and potential treatments for ubiquitous but neglected herpesvirus infections

Jonathan E Gable et al. Chem Rev. .
No abstract available

PubMed Disclaimer

Figures

Figure 1
Figure 1
Human herpesviruses, diseases, and antiherpesvirus treatments organized by subfamilies (α, β, and γ).
Figure 2
Figure 2
“Druggable” viral replication cycle. The processes of entry, viral DNA replication, encapsidation, capsid maturation, egress, and the role of viral kinases are depicted diagrammatically. Each process offers opportunities for inhibition of the viral replication cycle.
Figure 3
Figure 3
Approved guanosine analog inhibitors of herpesvirus replication (Figure 2, replication).
Figure 4
Figure 4
Additional inhibitors of the viral DNA polymerase (Figure 2, replication).
Figure 5
Figure 5
Bicyclic nucleoside analogs and a lipid ester analog of cidofovir. These inhibitors target viral replication (Figure 2, replication).
Figure 6
Figure 6
Helicase-primase inhibitors (Figure 2, replication).
Figure 7
Figure 7
Terminase inhibitors (Figure 2, encapsidation).
Figure 8
Figure 8
Portal vertex inhibitors (Figure 2, encapsidation).
Figure 9
Figure 9
Putative HCMV fusion inhibitors (Figure 2, entry).
Figure 10
Figure 10
Ribonucleotide reductase protein–protein interaction inhibitors and inhibitors of unknown mechanism.
Figure 11
Figure 11
Roscovitine, a cyclin dependent kinase (CDK) inhibitor, and HIV and HCV protease inhibitors.
Figure 12
Figure 12
Dimeric herpesvirus protease and its shallow binding pocket. HCMV protease (PDB: 1NJU) is depicted. Helices 2 (cyan), 5 (blue), and 6 (yellow) are critical to dimerization and allosteric activation of the enzyme. The shallow binding pocket (inset) is shown with a peptidomimetic inhibitor bound. The catalytic triad (Ser-His-His) is shown in green and the conserved arginines of the oxyanion whole in purple.
Figure 13
Figure 13
Overlay of known herpesvirus protease structures (HCMV, HSV2, EBV, VZV, and KSHV proteases).
Scheme 1
Scheme 1. Herpesvirus Protease Catalytic Mechanism and Ser-His-His Catalytic Triad
Figure 14
Figure 14
M- and R-site alignments for herpesvirus protease substrate specificity. WebLogo 3.3 was used to generate a specificity profile based on the M- and R-cleavage sites of KSHV, EBV, HHV-6, HCMV, HSV-1, and VZV assembly protein–protease fusion sequences.
Figure 15
Figure 15
General protease inhibitors and an HCMV pentafluoroethyl ketone inhibitor (Figure 2, capsid maturation).
Figure 16
Figure 16
β- and trans-lacatam herpesvirus protease inhibitors (Figure 2, capsid maturation).
Figure 17
Figure 17
Azetidine, benzoxazinone, thieno[2,3-d]oxazinone, spirocyclopropyl oxazolones, and benzylidine N-sulphonyloxyimidazolone mechanism-based herpesvirus protease inhibitors (Figure 2, capsid maturation).
Figure 18
Figure 18
Order-to-disorder transition of conserved oxyanion hole arginines upon dimer disruption.
Figure 19
Figure 19
Dimer disruptor 2 (DD2), an allosteric herpesvirus protease inhibitor (Figure 2, capsid maturation).
Scheme 2
Scheme 2. Potential Mechanism of Covalent Protease Inhibition by Imidazolones
Figure 20
Figure 20
Proposed mechanism of dimer disruption and allosteric inhibition of herpesvirus proteases. Inhibitor binding in the core of the protein precludes folding of the C-terminal helices, preventing both dimerization and proper formation of the oxyanion holes formed by two conserved arginines. The catalytic serine is unperturbed, but the substrate binding site may be occluded. Reprinted from ref (176). Copyright 2014 American Chemical Society.
See this image and copyright information in PMC

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