Beyond sole models for the first steps of Pt-DNA interactions: Fundamental properties of mono(nucleobase) adducts of PtII coordination compounds

Lippert, Bernhard; Miguel, Pablo J. Sanz

doi:10.1016/j.ccr.2022.214566

Cited by 8 publications

(2 citation statements)

References 224 publications

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“…In other words, these molecules hold the promise to be a new class of antitumor/antiviral antimetabolites, products of the merging of the two classes of platinum-based drugs and modified NAs. The suitability of this approach was confirmed by some previously reported studies evaluating the antitumor/antiviral properties of platinum-nucleos(t)ide compounds [ 11 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ].…”

Section: Introductionsupporting

confidence: 55%

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Castro

Ciardullo

Fanizzi

et al. 2023

IJMS

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In this work, we elucidated some key aspects of the mechanism of action of the cisplatin anticancer drug, cis-[Pt(NH3)2Cl2], involving direct interactions with free nucleotides. A comprehensive in silico molecular modeling analysis was conducted to compare the interactions of Thermus aquaticus (Taq) DNA polymerase with three distinct N7-platinated deoxyguanosine triphosphates: [Pt(dien)(N7-dGTP)] (1), cis-[Pt(NH3)2Cl(N7-dGTP)] (2), and cis-[Pt(NH3)2(H2O)(N7-dGTP)] (3) {dien = diethylenetriamine; dGTP = 5′-(2′-deoxy)-guanosine-triphosphate}, using canonical dGTP as a reference, in the presence of DNA. The goal was to elucidate the binding site interactions between Taq DNA polymerase and the tested nucleotide derivatives, providing valuable atomistic insights. Unbiased molecular dynamics simulations (200 ns for each complex) with explicit water molecules were performed on the four ternary complexes, yielding significant findings that contribute to a better understanding of experimental results. The molecular modeling highlighted the crucial role of a specific α-helix (O-helix) within the fingers subdomain, which facilitates the proper geometry for functional contacts between the incoming nucleotide and the DNA template needed for incorporation into the polymerase. The analysis revealed that complex 1 exhibits a much lower affinity for Taq DNA polymerase than complexes 2–3. The affinities of cisplatin metabolites 2–3 for Taq DNA polymerase were found to be quite similar to those of natural dGTP, resulting in a lower incorporation rate for complex 1 compared to complexes 2–3. These findings could have significant implications for the cisplatin mechanism of action, as the high intracellular availability of free nucleobases might promote the competitive incorporation of platinated nucleotides over direct cisplatin attachment to DNA. The study’s insights into the incorporation of platinated nucleotides into the Taq DNA polymerase active site suggest that the role of platinated nucleotides in the cisplatin mechanism of action may have been previously underestimated.

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Section: Introductionsupporting

confidence: 55%

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Castro

Ciardullo

Fanizzi

et al. 2023

IJMS

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“…They can act as prodrugs and, once introduced inside cells by the plasma membrane nucleoside transporters, require intracellular phosphorylation to generate their pharmacologically active triphosphate form [ 38 ]. Many investigations have focused on the study of the synthesis, structural features, and antitumor and/or antiviral biological effects of platinated nucleotides [ 74 , 79 , 89 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 ]. Recently, our research efforts were devoted to a deeper comprehension of the cellular metabolic mechanisms involving some model platinated nucleos(t)ides, to confirm their potential as antimetabolites.…”

Section: Cellular Processing Of Platinated Nucleotidesmentioning

confidence: 99%

Platinum-Nucleos(t)ide Compounds as Possible Antimetabolites for Antitumor/Antiviral Therapy: Properties and Perspectives

et al. 2023

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Nucleoside analogues (NAs) are a family of compounds which include a variety of purine and pyrimidine derivatives, widely used as anticancer and antiviral agents. For their ability to compete with physiological nucleosides, NAs act as antimetabolites exerting their activity by interfering with the synthesis of nucleic acids. Much progress in the comprehension of their molecular mechanisms has been made, including providing new strategies for potentiating anticancer/antiviral activity. Among these strategies, new platinum-NAs showing a good potential to improve the therapeutic indices of NAs have been synthesized and studied. This short review aims to describe the properties and future perspectives of platinum-NAs, proposing these complexes as a new class of antimetabolites.

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Janus Grotthuss‐Vehicle Mechanism Enhances Fast OH⁻ Transport for Ultralong Lifetime Flexible Zinc–Air Battery

Yang,

Sun,

et al. 2024

Adv Funct Materials

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The flexible zinc–air battery has garnered ever‐growing attentions in the current decade taking advantages of the high efficiency, environmentally friendliness, and safety features. However, the sluggish ion transport and poor mechanical property hinder its realistic and mass application. To address these challenges, this study proposes a Janus strategy which combines the Grotthuss and Vehicle mechanism for OH− transport in the gel by assembling the dual network gel with LDH (layer double hydroxides) in the gel's pores. The gel can sustain 530% strain and 0.19 MPa stress without significant plastic deformation and the as‐prepared battery exhibits the high ionic conductivity as 145.93 mS cm−1 and long lifetime over 160 h. The further simulation reveals that the Grotthuss mechanism plays the determine role in the ion transport, contributing to the fast OH− transport and highly efficient flexible zinc–air battery.

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Beyond sole models for the first steps of Pt-DNA interactions: Fundamental properties of mono(nucleobase) adducts of PtII coordination compounds

Cited by 8 publications

References 224 publications

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Platinum-Nucleos(t)ide Compounds as Possible Antimetabolites for Antitumor/Antiviral Therapy: Properties and Perspectives

Janus Grotthuss‐Vehicle Mechanism Enhances Fast OH⁻ Transport for Ultralong Lifetime Flexible Zinc–Air Battery

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Beyond sole models for the first steps of Pt-DNA interactions: Fundamental properties of mono(nucleobase) adducts of PtII coordination compounds

Cited by 8 publications

References 224 publications

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Incorporation of N7-Platinated Guanines into Thermus Aquaticus (Taq) DNA Polymerase: Atomistic Insights from Molecular Dynamics Simulations

Platinum-Nucleos(t)ide Compounds as Possible Antimetabolites for Antitumor/Antiviral Therapy: Properties and Perspectives

Janus Grotthuss‐Vehicle Mechanism Enhances Fast OH− Transport for Ultralong Lifetime Flexible Zinc–Air Battery

Contact Info

Product

Resources

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Janus Grotthuss‐Vehicle Mechanism Enhances Fast OH⁻ Transport for Ultralong Lifetime Flexible Zinc–Air Battery