Interactions of platinum(II)-derivatized triplex-forming oligonucleotides with DNA
Bibliographic record
Abstract
Polypyrimidine oligonucleotides can bind to tracts of contiguous purines in double-stranded DNA to form triple-stranded complexes. The stability of the triplex is reduced significantly if the target purine tract is interrupted by a single pyrimidine. Previous studies have shown that incorporation of an N4-aminoalkylcytosine into the triplex-forming oligonucleotide (TFO), opposite a single CG interruption, facilitates triplex formation. Examination of molecular models suggested that further modification of the amino group of the aminoalkyl arm might enable adduct formation with the N7 of the guanine of the CG interruption. To test this, we prepared 2′-deoxyribo-and 2′-O-methylribo-TFOs that contained cytosine (C), N4-(2-aminoethyl)cytosine (ae-C), or diethylenetriamineplatinum(II) (DPt-C) or cis-aquodiammineplatinum(II) (cPt-C) derivatives of N4-(2-aminoethyl)cytosine, positioned opposite a CG interruption of a polypurine tract found in the pol gene of HIV-1 proviral DNA. Although the C- and ae-C-derivatized deoxyribo-TFOs formed triplexes of modest stability and the DPt-C-modified TFO failed to form a triplex, the C- and ae-C-derivatized 2′-O-methylribo-TFOs formed remarkably stable triplexes (Tm = 57 °C). The DPt-C- and cPt-C-modified 2′-O-methylribo-TFOs also formed triplexes, although their stabilities were reduced (Tm = 33 °C), suggesting that the tethered platinum group may interfere sterically with TFO binding. Consistent with this hypothesis was the observation that triplex stability was restored (Tm = 57 °C) when the diethylenetriamineplatinum(II) group was tethered to the 5′-end of the 2′-O-methylribo-TFO via a 2-aminoethylcarbamate linkage. Taken together, these results suggest that 2′-O-methylribo-TFOs may be particularly useful in targeting purine tracts in DNA that have CG interruptions, and that further modification with platinum derivatives could lead to the design of TFOs that are capable of covalent binding to their target, thus increasing the effectiveness of the TFO.Key words: triplex-forming oligonucleotide, TFO, cisplatin, interrupted polypurine tract.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".