Thiated derivatives of 2′,3′-dideoxy-3′-fluorothymidine: Synthesis, in vitro anti-HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms

Miazga, Agnieszka; Hamy, François; Louvel, Séverine; Klimkait, Thomas; Pietrusiewicz, Zofia M.; Kurzyńska-Kokorniak, Anna; Figlerowicz, Marek; Wińska, Patrycja; Kulikowski, Tadeusz

doi:10.1016/j.antiviral.2011.05.012

Cited by 4 publications

(4 citation statements)

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“…A possible mechanism of an auto-regulatory feedback loop (right). tious diseases caused by such dangerous viruses as HIV or HCV (Figlerowicz et al, 2003;Kurzynska-Kokorniak et al, 2009;Miazga et al, 2011;Jackowiak et al, 2012;Gorska et al, 2013;Jackowiak et al, 2014;Dutkiewicz et al, 2015;Belter et al, 2016).…”

Section: Different Mechanisms Of the Hdicer Activity Regulation By Shmentioning

confidence: 99%

How short RNAs impact the human ribonuclease Dicer activity: putative regulatory feedback-loops and other RNA-mediated mechanisms controlling microRNA processing

et al. 2017

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Ribonuclease Dicer plays a pivotal role in RNA interference pathways by processing long double-stranded RNAs and single-stranded hairpin RNA precursors into small interfering RNAs (siRNAs) and microRNAs (miRNAs), respectively. While details of Dicer regulation by a variety of proteins are being elucidated, less is known about non-protein factors, e.g. RNA molecules, that may influence this enzyme's activity. Therefore, we decided to investigate the question of whether the RNA molecules can function not only as Dicer substrates but also as its regulators. Our previous in vitro studies indicated that the activity of human Dicer can be influenced by short RNA molecules that either bind to Dicer or interact with its substrates, or both. Those studies were carried out with commercial Dicer preparations. Nevertheless, such preparations are usually not homogeneous enough to carry out more detailed RNA-binding studies. Therefore, we have established our own system for the production of human Dicer in insect cells. In this manuscript, we characterize the RNA-binding and RNA-cleavage properties of the obtained preparation. We demonstrate that Dicer can efficiently bind single-stranded RNAs that are longer than ~20-nucleotides. Consequently, we revisit possible scenarios of Dicer regulation by single-stranded RNA species ranging from ~10- to ~60-nucleotides, in the context of their binding to this enzyme. Finally, we show that siRNA/miRNA-sized RNAs may affect miRNA production either by binding to Dicer or by participating in regulatory feedback-loops. Altogether, our studies suggest a broad regulatory role of short RNAs in Dicer functioning.

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Section: Different Mechanisms Of the Hdicer Activity Regulation By Shmentioning

confidence: 99%

How short RNAs impact the human ribonuclease Dicer activity: putative regulatory feedback-loops and other RNA-mediated mechanisms controlling microRNA processing

et al. 2017

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“…13 Intramolecular displacement of the 5 0 -tosylate by the C2-oxyanion formed in the presence of a Brønsted base (e.g., DBU) yielded the 2,5 0 -O-anhydro-cyclonucleoside, and subsequent ring-opening in refluxing ethanol afforded the 2-ethoxythymidine 3 in 59% overall yield from 1. After converting 3 into the acetate 4, we were able to incorporate the sulfur atom into the nucleobase using H 2 S in the presence of tetramethylguanidine (TMG) 14 (see Fig. S1 in the ESI † for details of the reaction setup).…”

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confidence: 99%

Synthesis of activated 3′-amino-3′-deoxy-2-thio-thymidine, a superior substrate for the nonenzymatic copying of nucleic acid templates

Izgu

Szostak

2016

Chem. Commun.

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We present a scalable synthesis of 3'-amino-3'-deoxy-2-thio-thymidine-5'-phosphoro-2-methylimidazolide, an activated monomer that can copy adenosine residues in nucleic acid templates rapidly without a polymerase. The sulfur atom substitution enhances the rate of template copying by 5-fold compared with the 3'-amino-3'-deoxy-T monomer, while the 3'-amino monomers exhibit a 2- to 30-fold enhancement compared with their ribonucleotide counterparts.

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“…FLTMP 6 was synthesized in analogy to described procedures, and the analytical data were identical to those reported …”

Section: Methodsmentioning

confidence: 99%

Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

et al. 2022

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3′-Fluoro-3′-deoxythymidine (FLT) was identified as one of the most potent inhibitors of human immunodeficiency virus (HIV) replication. However, FLT also showed severe toxicity so that it was abundant as a potential chemotherapeutic agent. Here, we describe various triphosphate prodrugs of FLT aiming for (a) a bypass of all phosphorylation steps needed to convert the nucleoside analogue into its triphosphate (TP) form, (b) an intracellular delivery of hydrolytically and enzymatically stable triphosphate derivatives, and (c) increasing the selectivity for HIV-RT vs three cellular DNA polymerases including the mitochondrial DNA polymerase γ. γ-Alkylated FLTTP compounds fulfill all of these requirements because these compounds proved highly resistant to dephosphorylation and showed strong selectivity for HIV-RT. Moreover, a prodrug form of these compounds proved to be nontoxic in CEM cells.

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Thiated derivatives of 2′,3′-dideoxy-3′-fluorothymidine: Synthesis, in vitro anti-HIV-1 activity and interaction with recombinant drug resistant HIV-1 reverse transcriptase forms

Cited by 4 publications

References 20 publications

How short RNAs impact the human ribonuclease Dicer activity: putative regulatory feedback-loops and other RNA-mediated mechanisms controlling microRNA processing

How short RNAs impact the human ribonuclease Dicer activity: putative regulatory feedback-loops and other RNA-mediated mechanisms controlling microRNA processing

Synthesis of activated 3′-amino-3′-deoxy-2-thio-thymidine, a superior substrate for the nonenzymatic copying of nucleic acid templates

Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

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