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Specific recognition by the tripeptide lysyl-tryptophyl-alpha-lysine of structural damage induced in DNA by platinum
Abstract:
The antitumoral derivative cisPt binds to DNA, as do its inactive analogs, trans- and dienPt. Structural damage introduced into DNA after reaction with the Pt derivatives were probed by using the peptide LysTrpLys. This peptide was used for its preferential binding to single-stranded structures (Brun, F., Toulmé, J.J. and Hélène, C. (1975) Biochemistry 14, 558-563). Phosphorescence lifetime measurements show that the Pt-induced heavy atom effects are quite similar in the three peptide-DNA-Pt complexes whatever the nature of the Pt derivative used. In contrast, fluorescence quenching strongly depends on the nature of the Pt derivatives. This quenching was therefore attributed to the stacking interactions engaged by the tryptophan residue with nucleic acid bases. A comparison of fluorescence quenching data for native and modified DNAs demonstrates that modification by dienPt has no effect on stacking interactions and that high levels of modifications by trans Pt are required to observe a change in stacking efficiency. In contrast modification by cis Pt induces the formation of strong stacking sites. The results strongly suggest the existence of locally opened regions in DNA modified by cis Pt.
Insights
The antitumoral drug cisPt opens DNA structures, unlike its inactive analogs transPt and dienPt. This DNA opening by cisPt is crucial for its therapeutic effects, differentiating it from other platinum derivatives.
Area of Science:
- Biochemistry
- Molecular Biology
- Medicinal Chemistry
Background:
- Platinum-based drugs are vital anticancer agents.
- The mechanism of action for platinum derivatives involves DNA binding.
- Understanding structural DNA changes induced by platinum compounds is key to drug development.
Purpose of the Study:
- To investigate the structural modifications of DNA induced by different platinum (Pt) derivatives.
- To compare the effects of cisPt, transPt, and dienPt on DNA structure using a specific peptide probe.
- To elucidate the relationship between DNA structural changes and the activity of Pt-based anticancer drugs.
Main Methods:
- Utilized the peptide LysTrpLys, which preferentially binds to single-stranded DNA.
- Employed phosphorescence lifetime measurements to assess Pt-induced heavy atom effects.
- Applied fluorescence quenching assays to evaluate changes in DNA base stacking interactions.
Main Results:
- Phosphorescence data indicated similar Pt-induced heavy atom effects across all tested Pt derivatives.
- Fluorescence quenching revealed that cisPt significantly alters tryptophan-DNA base stacking interactions.
- dienPt showed no effect on stacking, while transPt required high modification levels to alter stacking efficiency.
Conclusions:
- cisPt induces significant structural changes in DNA, leading to locally opened regions.
- The differential effects of Pt derivatives on DNA stacking interactions correlate with their antitumoral activity.
- These findings highlight the importance of specific DNA structural modifications for cisPt's efficacy.