In vitro evaluation of phosphorothioate oligonucleotides targeted to the E2 mRNA of papillomavirus: potential treatment for genital warts.

Abstract

Papillomaviruses induce benign proliferative lesions, such as genital warts, in humans. The E2 gene product is thought to play a major role in the regulation of viral transcription and DNA replication and may represent a rational target for an antisense oligonucleotide drug action. Phosphorothioate oligonucleotides complementary to E2 mRNAs were synthesized and tested in a series of in vitro bovine papillomavirus (BPV) and human papillomavirus (HPV) models for the ability to inhibit E2 transactivation and virus-induced focus formation. The most active BPV-specific compounds were complementary to the mRNA cap region (ISIS 1751), the translation initiation region for the full-length E2 transactivator (ISIS 1753), and the translation initiation region for the E2 transrepressor mRNA (ISIS 1755). ISIS 1751 and ISIS 1753 were found to reduce E2-dependent transactivation and viral focus formation in a sequence-specific and concentration-dependent manner. ISIS 1755 increased E2 transactivation in a dose-dependent manner but had no effect on focus formation. Oligonucleotides with a chain length of 20 residues had optimal activity in the E2 transactivation assay. On the basis of the above observations, ISIS 2105, a 20-residue phosphorothioate oligonucleotide targeted to the translation initiation of both HPV type 6 (HPV-6) and HPV-11 E2 mRNA, was designed and shown to inhibit E2-dependent transactivation by HPV-11 E2 expressed from a surrogate promoter. These observations support the rationale of E2 as a target for antiviral therapy against papillomavirus infections and specifically identify ISIS 2105 as a candidate antisense oligonucleotide for the treatment of genital warts induced by HPV-6 and HPV-11.

• Authors: L M Cowsert, M C Fox, G Zon, C K Mirabelli
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 37 Issue 2 Pg. 171-7 (Feb 1993) ISSN: 0066-4804 [Print] United States
• PMID: 8383937 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• DNA-Binding Proteins
• E2 protein, Bovine papillomavirus
• RNA Caps
• RNA, Antisense
• RNA, Messenger
• RNA, Viral
• Thionucleotides
• Viral Proteins
• Ribonuclease H

Topics

• Animals
• Antiviral Agents (therapeutic use)
• Base Sequence
• Bovine papillomavirus 1 (drug effects, genetics)
• Condylomata Acuminata (drug therapy, genetics)
• DNA-Binding Proteins (genetics)
• Mice
• Molecular Sequence Data
• Nucleic Acid Hybridization
• Papillomaviridae (drug effects, genetics)
• RNA Caps (metabolism)
• RNA, Antisense (genetics)
• RNA, Messenger (genetics)
• RNA, Viral (genetics)
• Ribonuclease H (metabolism)
• Thionucleotides (therapeutic use)
• Transcriptional Activation (drug effects)
• Viral Proteins (genetics)