We have previously shown that an oligo(nucleoside methylphosphonate) (deoxynucleoside methylphosphonate residues in italics) complementary to the acceptor splice junction of herpes simplex virus type 1 (HSV-1) immediate-early (IE) pre-mRNAs 4,5 [d(TpTCCTCCTGCGG)], causes sequence-specific inhibition of virus growth in infected cell cultures (Smith et al., 1986; Kulka et al., 1989). Here we report a similar inhibition of HSV-1 growth by oligo(nucleoside methylphosphonates) complementary to the splice donor site of HSV-1 IE pre-mRNAs 4,5 [d(GpCTTACCCGTGC)] and to the translation initiation site of IE4 mRNA [d(ApATGTCGGCCAT)]. An oligomer complementary to the translation initiation site of IE5 mRNA [d(GpGCCCACGACAT)] or an unrelated oligomer [d(GpCGGGAAGGCAC)] did not inhibit virus growth. IC50 values were 20, 25 and 20 microM for d(TpTCCTCCTGCGG), d(GpCTTACCCGTGC) and d(ApATGTCGGCCAT) respectively. In infected BALB/c mice d(TpTCCTCCTGCGG) caused a significant decrease in HSV-1 growth (82% inhibition at 500 microM). A psoralen-derivative of d(TpTCCTCCTGCGG) that binds covalently to complementary sequences after exposure to 365 nm irradiation, inhibited HSV-1 growth (86-91%) at a 10-fold lower concentration than the non-derivatized oligomer. The inhibition was sequence-specific and significantly lower (27%) for HSV-2 that differs from HSV-1 in 7 of the 12 bases targeted by d(TpTCCTCCTGCGG). Virus growth was not inhibited by d(GpGCCCACGACAT). The data suggest that oligo(nucleoside methylphosphonates) may be effective antiviral agents.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/0166-3542(93)90002-z | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Triplex formation by psoralen-conjugated chimeric oligonucleoside methylphosphonates.
Biochemistry
July 2000
Department of Biochemistry and Molecular Biology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Interactions between nuclease-resistant, 5'-psoralen-conjugated, chimeric methylphosphonate oligodeoxyribo- or oligo-2'-O-methylribo-triplex-forming oligomers (TFOs) and a purine tract found in the envelope gene of HIV proviral DNA (env-DNA) were investigated by gel mobility shift assays or by photo-cross-linking experiments. These chimeric TFOs contain mixtures of methylphosphonate and phosphodiester internucleotide bonds. A pyrimidine chimeric TFO composed of thymidine and 5-methyl-2'-deoxycytidine (C), d-PS-TpCpTpCpTpCpTpTpTpTpTpTpCpTpC (1mp) where PS is trimethylpsoralen and p is methylphosphonate, forms a stable triplex with env-DNA whose dissociation constant is 1.
View Article and Find Full Text PDFSyntheses of alternating oligo-2'-O-methylribonucleoside methylphosphonates and their interactions with HIV TAR RNA.
Biochemistry
November 1999
Department of Biochemistry and Molecular Biology, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Oligonucleotide analogues 15-20 nucleotides in length have been prepared, whose sequences are complementary to nucleotides in the upper hairpin of HIV TAR RNA. These alternating oligonucleoside methylphosphonates, mr-AOMPs, contain 2'-O-methylribonucleosides and alternating methylphosphonate and phosphodiester internucleotide linkages. The methylphosphonate and phosphodiester linkages of these oligomers are highly resistant to hydrolysis by exonuclease activity found in mammalian serum and to endonucleases, such as S1 nuclease.
View Article and Find Full Text PDFApplication of oligonucleoside methylphosphonates in the studies on phosphodiester hydrolysis by Serratia endonuclease.
Nucleosides Nucleotides
September 1999
Division of Biopolymers, Central Drug Research Institute, Lucknow, India.
The endonuclease from Serratia marcescens is a non-specific enzyme that cleaves single and double stranded RNA and DNA. It accepts a phosphorylated pentanucleotide as a minimal substrate which is cleaved in the presence of Mg2+ at the second phosphodiester linkage. The present study is aimed at understanding the role of electrostatic and hydrogen bond interactions in phosphodiester hydrolysis.
View Article and Find Full Text PDFAnomeric inversion (from beta to alpha) in methylphosphonate oligonucleosides enhances their affinity for DNA and RNA.
Nucleic Acids Res
October 1998
Laboratoire de Chimie Bio-organique, CC008, UMR 5625 CNRS-UM II, Université Montpellier II, Place Eugène Bataillon, 34095 Montpellier Cedex 5, France.
Here we report that the poor binding of methylphosphonate oligodeoxynucleosides (MP-ODNs) to their nucleic acid targets can be improved by additional inversion of the anomeric configuration (from beta to alpha) in the sugar moieties to give a new class of analogs, MP alpha-oligonucleosides. MP alpha-dT12and MP 5' alpha-d(TCTTAACCCACA) 3' were synthesized and their ability to form hybrids with complementary single stranded (ss)DNA and ssRNA, as well as with double stranded (ds)DNA, was evaluated. The thermal stability of hybrids formed with MP alpha-analogs was compared with the affinity of phosphodiester (PO) and phosphorothioate (PS) beta- and alpha-oligomers for their targets.
View Article and Find Full Text PDFInhibition of human collagenase activity by antisense oligonucleoside methylphosphonates.
Antisense Nucleic Acid Drug Dev
April 1997
Department of Biochemistry, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Oligodeoxyribonucleoside methylphosphonates (d-OMP) were synthesized whose sequences are complementary to sequences found in the mRNA coding for the 72-kDa (MMP-2) or 92-kDA (MMP-9) forms of human collagenase i.v., matrix metalloproteinases (MMP) whose excessive secretion correlates with the metastatic potential of tumor cells.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!