Cell-permeable artificial zinc-finger proteins as potent antiviral drugs for human papillomaviruses

Cell-permeable artificial zinc-finger proteins as potent antiviral drugs for human papillomaviruses Human papillomavirus (HPV) is one of the important pharmaceutical targets because infection of the high-risk types causes invasive cervical cancer. However, effective antiviral drugs for HPV have not been developed so far. In the present study, we constructed cell-permeable artificial zinc-finger proteins (AZPs) by fusing an AZP previously generated for inhibition of HPV-18 DNA replication with a cell-penetrating peptide (CPP) as candidates for new antiviral drugs against HPV. We confirmed that these CPP–AZP fusions reduced the replication rate in transient replication assays when added to the culture medium. In particular, 250 nM CPP–AZP (designated AZP-R9) containing a 9-mer of arginine as the CPP reduced HPV-18 DNA replication to 3% of that of a control, and the 50% effective concentration (EC 50 ) was <31 nM. Furthermore, a cytotoxicity assay revealed that the 50% inhibitory concentration (IC 50 ) of AZP-R9 was >10 μM. Therefore, the selectivity index, defined as IC 50 /EC 50 , was >300, which is better than that of the antiviral cidofovir for HPVs. Thus, our results demonstrate that cell-permeable AZPs could serve as potent protein-based antiviral drugs. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Virology Springer Journals

Cell-permeable artificial zinc-finger proteins as potent antiviral drugs for human papillomaviruses

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Publisher
Springer Vienna
Copyright
Copyright © 2008 by Springer-Verlag
Subject
Biomedicine; Infectious Diseases; Medical Microbiology ; Virology
ISSN
0304-8608
eISSN
1432-8798
D.O.I.
10.1007/s00705-008-0125-7
Publisher site
See Article on Publisher Site

Abstract

Human papillomavirus (HPV) is one of the important pharmaceutical targets because infection of the high-risk types causes invasive cervical cancer. However, effective antiviral drugs for HPV have not been developed so far. In the present study, we constructed cell-permeable artificial zinc-finger proteins (AZPs) by fusing an AZP previously generated for inhibition of HPV-18 DNA replication with a cell-penetrating peptide (CPP) as candidates for new antiviral drugs against HPV. We confirmed that these CPP–AZP fusions reduced the replication rate in transient replication assays when added to the culture medium. In particular, 250 nM CPP–AZP (designated AZP-R9) containing a 9-mer of arginine as the CPP reduced HPV-18 DNA replication to 3% of that of a control, and the 50% effective concentration (EC 50 ) was <31 nM. Furthermore, a cytotoxicity assay revealed that the 50% inhibitory concentration (IC 50 ) of AZP-R9 was >10 μM. Therefore, the selectivity index, defined as IC 50 /EC 50 , was >300, which is better than that of the antiviral cidofovir for HPVs. Thus, our results demonstrate that cell-permeable AZPs could serve as potent protein-based antiviral drugs.

Journal

Archives of VirologySpringer Journals

Published: Jul 1, 2008

References

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