TY - JOUR
T1 - Cell-permeable artificial zinc-finger proteins as potent antiviral drugs for human papillomaviruses
AU - Mino, Takashi
AU - Mori, Tomoaki
AU - Aoyama, Yasuhiro
AU - Sera, Takashi
N1 - Funding Information:
We thank Tadayuki Imanaka and Haruyuki Atomi for the use of their DNA sequencer. This work was supported in part by Grants-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (No. 17550154 to T.S.).
PY - 2008/7
Y1 - 2008/7
N2 - 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 (EC50) was <31 nM. Furthermore, a cytotoxicity assay revealed that the 50% inhibitory concentration (IC50) of AZP-R9 was >10 μM. Therefore, the selectivity index, defined as IC50/EC50, 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.
AB - 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 (EC50) was <31 nM. Furthermore, a cytotoxicity assay revealed that the 50% inhibitory concentration (IC50) of AZP-R9 was >10 μM. Therefore, the selectivity index, defined as IC50/EC50, 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.
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U2 - 10.1007/s00705-008-0125-7
DO - 10.1007/s00705-008-0125-7
M3 - Article
C2 - 18521532
AN - SCOPUS:45849133735
SN - 0304-8608
VL - 153
SP - 1291
EP - 1298
JO - Archives of Virology
JF - Archives of Virology
IS - 7
ER -
