Inhibition of human immunodeficiency virus type 1 replication by P‐stereodefined oligo(nucleoside phosphorothioate)s in a long‐term infection model

Inagawa, Takabumi; Nakashima, Hideki; Karwowski, Bolesław T.; Guga, Piotr; Stec, Wojciech J.; Takeuchi, Hiroaki; Takaku, Hiroshi

doi:10.1016/s0014-5793(02)03235-0

Cited by 14 publications

(11 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PS-ODNs of mixed diastereomeric linkages show intermediate abilities [ 163 , 164 ]. It has been indicated that nuclease stability is one of the most important factors for PS-ODN efficacy [ 165 ], and hence the stereocontrolled synthesis of antisense PS-ODNs has been well investigated (for a review see [ 163 ]).…”

Section: Antisense Oligonucleotides Analogues and Mimicsmentioning

confidence: 99%

Hitting bacteria at the heart of the central dogma: sequence-specific inhibition

2007

View full text Add to dashboard Cite

An important objective in developing new drugs is the achievement of high specificity to maximize curing effect and minimize side-effects, and high specificity is an integral part of the antisense approach. The antisense techniques have been extensively developed from the application of simple long, regular antisense RNA (asRNA) molecules to highly modified versions conferring resistance to nucleases, stability of hybrid formation and other beneficial characteristics, though still preserving the specificity of the original nucleic acids. These new and improved second-and thirdgeneration antisense molecules have shown promising results. The first antisense drug has been approved and more are in clinical trials. However, these antisense drugs are mainly designed for the treatment of different human cancers and other human diseases. Applying antisense gene silencing and exploiting RNA interference (RNAi) are highly developed approaches in many eukaryotic systems. But in bacteria RNAi is absent, and gene silencing by antisense compounds is not nearly as well developed, despite its great potential and the intriguing possibility of applying antisense molecules in the fight against multiresistant bacteria. Recent breakthrough and current status on the development of antisense gene silencing in bacteria including especially phosphorothioate oligonucleotides (PS-ODNs), peptide nucleic acids (PNAs) and phosphorodiamidate morpholino oligomers (PMOs) will be presented in this review.

show abstract

Section: Antisense Oligonucleotides Analogues and Mimicsmentioning

confidence: 99%

Hitting bacteria at the heart of the central dogma: sequence-specific inhibition

2007

View full text Add to dashboard Cite

show abstract

“…One such example is the phosphorothioate oligodeoxyribonucleotides (PS‐ODNs) obtained by replacing one of the nonbridging oxygens of the phosphodiester bonds of DNA with sulphur (Rasmussen et al , 2007). Nuclease stability is one of the most important characteristics of PS‐ODNs (Inagawa et al , 2002). Their mechanism of action involves the binding to target mRNA and the activation of RNase H, resulting in mRNA degradation.…”

Section: Introductionmentioning

confidence: 99%

Zoocin A facilitates the entry of antisense constructs into Streptococcus mutans

Dufour

McLeod

Simmonds

2011

FEMS Microbiology Letters

View full text Add to dashboard Cite

The use of antisense oligodeoxyribonucleotides (asODNs) to inhibit gene function has proven to be an extremely powerful tool for establishing gene-function relationships. Diffusion limitations imposed by the thick peptidoglycan layer of Gram-positive bacteria have proven difficult to overcome for permeability of asODNs. Typically, introduction of the asODN is achieved by cloning the antisense sequence into a vector downstream of an inducible promoter and transforming this construct into the cell of interest. In this study, we report that the use of the streptococcolytic enzyme zoocin A facilitated entry of phosphorothioate oligodeoxyribonucleotides (PS-ODNs) into Streptococcus mutans, such that the degree of phenotypic response (cell growth inhibition) observed was sequence specific and correlated with the amount of zoocin A (R(2) =0.9919) or PS-ODN (R(2) =0.9928) used. Quantitative reverse transcriptase PCR was used to demonstrate that only the expression of the target gene against which the PS-ODN was designed was affected. We believe that the use of an appropriate bacteriolytic enzyme to facilitate entry of asODNs into bacterial cells provides a method that will be generally useful in the study of gene regulation in Gram-positive bacteria.

show abstract

“…The influence of the sense of P-chirality of PS-oligos upon their antiviral activity was tested by Takaku and co-workers, who showed that the 28 mer [All-S P -PS]-d(CGCTCTCGCTCCCATCTC TCTCCTTCTA) directed to the gag mRNA completely suppressed the expression of the HIV-1 gag p24 antigen in long-term HIV-1 infected cells for 30 days [199]. In contrast, the cells treated with [All-R P ]-oligomer showed a high level of HIV-1 replication at 16 days.…”

Section: Cccgggagaaga C a A A Aaaactctacgc 5'mentioning

confidence: 99%

P-Chiral Oligonucleotides in Biological Recognition Processes

Guga

2007

CTMC

Self Cite

View full text Add to dashboard Cite

Internucleotide phosphodiester linkages in non-modified oligonucleotides are quickly degraded by nucleolytic enzymes present in the cells and this feature practically eliminates natural DNA and RNA molecules from medical applications and from many structural and mechanistic studies. P-chiral oligonucleotide analogs, in which one of the non-bridging phosphate oxygen atoms is substituted with another heteroatom (e.g. S, Se) or a chemical group (e.g. CH3, BH3(-)), have significantly greater nuclease resistance and also offer important possibilities for detailed studies of interactions with other biomolecules at the molecular level. Notably, these substitutions do not disrupt hydrogen bonding between nucleobases and affect the overall geometry of the oligomers to only low or moderate extent, although important changes of hydration patterns and changes of interactions with metal ions are observed. Such the probes, including isotopomeric species labeled with a heavy oxygen isotope, possessing phosphorus atoms of selected absolute configurations, have been used for elucidation of the mode of action of many enzymes (nucleases, transferases, kinases), ribozymes and DNA-zymes, as well as for investigations on thermodynamic stability of nucleic acids complexes (duplexes, triplexes, i-motif) and for studies on a mechanism of conformational changes of B-Z type. They are also useful tools for analysis of interactions of the phosphoryl oxygen atoms in natural precursors with functional groups of proteins. The synthetic routes to stereodefined forms of selected types of P-chiral oligonucleotides are presented, as well as recently developed methods for their configurational analysis at micromolar concentration. Selected examples of application of diastereomerically pure P-chiral oligonucleotides for structural, biochemical and biological experiments are discussed.

show abstract

Inhibition of human immunodeficiency virus type 1 replication by P‐stereodefined oligo(nucleoside phosphorothioate)s in a long‐term infection model

Cited by 14 publications

References 33 publications

Hitting bacteria at the heart of the central dogma: sequence-specific inhibition

Hitting bacteria at the heart of the central dogma: sequence-specific inhibition

Zoocin A facilitates the entry of antisense constructs into Streptococcus mutans

P-Chiral Oligonucleotides in Biological Recognition Processes

Contact Info

Product

Resources

About