Novel Short Oligonucleotide Conjugates as Inhibitors of Human Telomerase

Krisztina Pongracz; Shihong Li; Brittney-Shea Herbert; Ronald Pruzan; Ellen Wunder; Allison Chin; Mieczyslaw Piatyszek; Jerry Shay; Sergei M. Gryaznov

doi:10.1002/chin.200409200

Novel Short Oligonucleotide Conjugates as Inhibitors of Human Telomerase

Nucleosides Nucleotides & Nucleic Acids ◽

10.1081/ncn-120023085 ◽

2003 ◽

Vol 22 (5-8) ◽

pp. 1627-1629 ◽

Cited By ~ 7

Author(s):

Krisztina Pongracz ◽

Shihong Li ◽

Brittney-Shea Herbert ◽

Ronald Pruzan ◽

Ellen Wunder ◽

...

Keyword(s):

Short Oligonucleotide ◽

Human Telomerase ◽

Oligonucleotide Conjugates

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Site-Specific Cleavage of RNAs Derived from the PIM1 3′-UTR by a Metal-Free Artificial Ribonuclease

Molecules ◽

10.3390/molecules24040807 ◽

2019 ◽

Vol 24 (4) ◽

pp. 807 ◽

Cited By ~ 3

Author(s):

Felix Zellmann ◽

Laura Thomas ◽

Ute Scheffer ◽

Roland Hartmann ◽

Michael Göbel

Keyword(s):

Competitive Inhibition ◽

Reaction Rates ◽

Phosphate Esters ◽

Rna Cleavage ◽

Site Specificity ◽

Cleavage Rate ◽

Short Oligonucleotide ◽

A Cell ◽

Artificial Nuclease ◽

Oligonucleotide Conjugates

Oligonucleotide conjugates of tris(2-aminobenzimidazole) have been reported previously to cleave complementary RNA strands with high levels of sequence and site specificity. The RNA substrates used in these studies were oligonucleotides not longer than 29-mers. Here we show that ~150–400-mer model transcripts derived from the 3′-untranslated region of the PIM1 mRNA reacted with rates and specificities comparable to those of short oligonucleotide substrates. The replacement of DNA by DNA/LNA mixmers further increased the cleavage rate. Tris(2-aminobenzimidazoles) were designed to interact with phosphates and phosphate esters. A cell, however, contains large amounts of phosphorylated species that may cause competitive inhibition of RNA cleavage. It is thus important to note that no loss in reaction rates was observed in phosphate buffer. This opens the way to in-cell applications for this type of artificial nuclease. Furthermore, we disclose a new synthetic method giving access to tris(2-aminobenzimidazoles) in multigram amounts.

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Evaluation of Floxuridine Oligonucleotide Conjugates Carrying Potential Enhancers of Cellular Uptake

International Journal of Molecular Sciences ◽

10.3390/ijms22115678 ◽

2021 ◽

Vol 22 (11) ◽

pp. 5678

Author(s):

Anna Aviñó ◽

Anna Clua ◽

Maria José Bleda ◽

Ramon Eritja ◽

Carme Fàbrega

Keyword(s):

Folic Acid ◽

Cellular Uptake ◽

Antiproliferative Activity ◽

Biological Effects ◽

Metabolic Activation ◽

Receptor Ligands ◽

Short Oligonucleotide ◽

Anti Cancer ◽

Small Molecule Enhancers ◽

Oligonucleotide Conjugates

Conjugation of small molecules such as lipids or receptor ligands to anti-cancer drugs has been used to improve their pharmacological properties. In this work, we studied the biological effects of several small-molecule enhancers into a short oligonucleotide made of five floxuridine units. Specifically, we studied adding cholesterol, palmitic acid, polyethyleneglycol (PEG 1000), folic acid and triantennary N-acetylgalactosamine (GalNAc) as potential enhancers of cellular uptake. As expected, all these molecules increased the internalization efficiency with different degrees depending on the cell line. The conjugates showed antiproliferative activity due to their metabolic activation by nuclease degradation generating floxuridine monophosphate. The cytotoxicity and apoptosis assays showed an increase in the anti-cancer activity of the conjugates related to the floxuridine oligomer, but this effect did not correlate with the internalization results. Palmitic and folic acid conjugates provide the highest antiproliferative activity without having the highest internalization results. On the contrary, cholesterol oligomers that were the best-internalized oligomers had poor antiproliferative activity, even worse than the unmodified floxuridine oligomer. Especially relevant is the effect induced by palmitic and folic acid derivatives generating the most active drugs. These results are of special interest for delivering other therapeutic oligonucleotides.

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