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Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA.

ABSTRACT: G-Quadruplex DNA structures have attracted increasing attention due to their biological roles and potential as targets for the development of new drugs. While most guanine-rich sequences in the genome have the potential to form monomeric G-quadruplexes, certain sequences have enough guanine-tracks to give rise to multimeric quadruplexes. One of these sequences is the human telomere where tandem repeats of TTAGGG can lead to the formation of two or more adjacent G-quadruplexes. Herein we report on the modular synthesis via click chemistry of dimeric metal-salphen complexes (with Ni^II and Pt^II) bridged by either polyether or peptide linkers. We show by circular dichroism (CD) spectroscopy that they generally have higher selectivity for dimeric vs monomeric G-quadruplexes. The emissive properties of the Pt^II-salphen dimeric complexes have been used to study their interactions with monomeric and dimeric G-quadruplexes in vitro as well as to study their cellular uptake and localization.

SUBMITTER: Kench T

PROVIDER: S-EPMC10197068 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA.

Kench Timothy T Rakers Viktoria V Bouzada David D Gomez-González Jacobo J Robinson Jenna J Kuimova Marina K MK Vázquez López Miguel M Vázquez M Eugenio ME Vilar Ramon R

Bioconjugate chemistry 20230429 5

G-Quadruplex DNA structures have attracted increasing attention due to their biological roles and potential as targets for the development of new drugs. While most guanine-rich sequences in the genome have the potential to form monomeric G-quadruplexes, certain sequences have enough guanine-tracks to give rise to multimeric quadruplexes. One of these sequences is the human telomere where tandem repeats of TTAGGG can lead to the formation of two or more adjacent G-quadruplexes. Herein we report o ...[more]

PMID: 37119235

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Project description:Molecular interactions between viral DNA and viral-encoded protein are a prerequisite for successful herpesvirus replication and production of new infectious virions. Here, we examined how the essential Kaposi's sarcoma-associated herpesvirus (KSHV) protein, RTA, binds to viral DNA using transmission electron microscopy (TEM). Previous studies using gel-based approaches to characterize RTA binding are important for studying the predominant form(s) of RTA within a population and identifying the DNA sequences that RTA binds with high affinity. However, using TEM we were able to examine individual protein-DNA complexes and capture the various oligomeric states of RTA when bound to DNA. Hundreds of images of individual DNA and protein molecules were collected and then quantified to map the DNA binding positions of RTA bound to the two KSHV lytic origins of replication encoded within the KSHV genome. The relative size of RTA or RTA bound to DNA were then compared to protein standards to determine whether RTA complexed with DNA was monomeric, dimeric, or formed larger oligomeric structures. We successfully analyzed a highly heterogenous dataset and identified new binding sites for RTA. This provides direct evidence that RTA forms dimers and high order multimers when bound to KSHV origin of replication DNA sequences. This work expands our understanding of RTA binding, and demonstrates the importance of employing methodologies that can characterize highly heterogenic populations of proteins.ImportanceKaposi's sarcoma-associated herpesvirus (KSHV) is a human herpesvirus associated with several human cancers, typically in patients with compromised immune systems. Herpesviruses establish lifelong infections in hosts in part due to the two phases of infection: the dormant and active phases. Effective antiviral treatments to prevent the production of new viruses are needed to treat KSHV. A detailed microscopy-based investigation of the molecular interactions between viral protein and viral DNA revealed how protein-protein interactions play a role in DNA binding specificity. This analysis will lead to a more in depth understanding of KSHV DNA replication and serve as the basis for anti-viral therapies that disrupt and prevent the protein-DNA interactions, thereby decreasing spread to new hosts.

Dataset Information

Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA.

Publications

Dimeric Metal-Salphen Complexes Which Target Multimeric G-Quadruplex DNA.

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