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1. Functionalizing DNA nanostructures for therapeutic applications

   https://doi.org/10.1002/wnan.1729  

   Henry, Skylar J. W. ; Stephanopoulos, Nicholas ( May 2021 , WIREs Nanomedicine and Nanobiotechnology)

   Recent advances in nanotechnology have enabled rapid progress in many areas of biomedical research, including drug delivery, targeted therapies, imaging, and sensing. The emerging field of DNA nanotechnology, in which oligonucleotides are designed to self‐assemble into programmable 2D and 3D nanostructures, offers great promise for further advancements in biomedicine. DNA nanostructures present highly addressable and functionally diverse platforms for biological applications due to their ease of construction, controllable architecture and size/shape, and multiple avenues for chemical modification. Both supramolecular and covalent modification with small molecules and polymers have been shown to expand or enhance the functions of DNA nanostructures in biological contexts. These alterations include the addition of small molecule, protein, or nucleic acid moieties that enable structural stability under physiological conditions, more efficient cellular uptake and targeting, delivery of various molecular cargos, stimulus‐responsive behaviors, or modulation of a host immune response. Herein, various types of DNA nanostructure modifications and their functional consequences are examined, followed by a brief discussion of the future opportunities for functionalized DNA nanostructures as well as the barriers that must be overcome before their translational use.

   This article is categorized under:

   Nanotechnology Approaches to Biology > Nanoscale Systems in Biology

   Therapeutic Approaches and Drug Discovery > Emerging Technologies

   Biology‐Inspired Nanomaterials > Nucleic Acid‐Based Structures

    

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2. Time-Dependent Density Functional Theory Calculations of 4-Thiothymidine-Containing DNA Dinucleotides

   https://doi.org/10.26434/chemrxiv.8224292  

   Luong, D. ; Ortiz-Rodríguez, L. A. ; Crespo-Hernández, C. E. ( January 2019 , ChemRxiv)

   The substitution of an oxygen atom in an exocyclic carbonyl group of the nucleobases by a sulfur atom in a nucleic acid base generates a thiobase. This substitution causes a redshift in the absorption spectrum of the thiobase with respect to the canonical nucleobase, moving the strongly allowed absorption band from the UVC to the UVA region of the electromagnetic spectrum. Due to this redshift and the efficient population of the triplet state, 4-thiothymidine (4tThd) can be selectively excited without exciting canonical DNA, making it a powerful UVA photosensitizer. The synergistic toxicity of 4tThd and UVA radiation allows for the enhanced killing of skin cancer cells. As a result, 4tThd has been proposed for use in conjunction with UVA radiation as potential photodynamic therapy agent, due to its photochemical properties and to a diminished cytotoxicity. Studies of the monomer 4tThd have been performed to explore the prospective use of 4tThd in photochemotherapeutic application with reduced phototoxic side effects. One study of 4tThd in aqueous solution proposed the main kinetic mechanism to consist of intersystem crossing from the S2 state to the triplet manifold. Vertical excitation energies were calculated using the optimized ground state of 4tThd in water and vacuum. These were found to be in good agreement with the values previously reported. After studying the monomer, the next step is to understand what happens when 4tThd interacts with the DNA bases. Therefore, ground state optimizations and vertical excitation energies calculations were performed for a series of 4tThd-containing dinucleotides. These vertical excitation energy calculations predict the order electronic states and likely kinetic mechanisms when 4tThd is incorporated into DNA, which will greatly assist in the interpretation of planned time-resolved experiments. 

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3. Structural Biology of the HEAT‐Like Repeat Family of DNA Glycosylases

   https://doi.org/10.1002/bies.201800133  

   Shi, Rongxin ; Shen, Xing‐Xing ; Rokas, Antonis ; Eichman, Brandt F. ( September 2018 , BioEssays)

   DNA glycosylases remove aberrant DNA nucleobases as the first enzymatic step of the base excision repair (BER) pathway. The alkyl‐DNA glycosylases AlkC and AlkD adopt a unique structure based on α‐helical HEAT repeats. Both enzymes identify and excise their substrates without a base‐flipping mechanism used by other glycosylases and nucleic acid processing proteins to access nucleobases that are otherwise stacked inside the double‐helix. Consequently, these glycosylases act on a variety of cationic nucleobase modifications, including bulky adducts, not previously associated with BER. The related non‐enzymatic HEAT‐like repeat (HLR) proteins, AlkD2, and AlkF, have unique nucleic acid binding properties that expand the functions of this relatively new protein superfamily beyond DNA repair. Here, we review the phylogeny, biochemistry, and structures of the HLR proteins, which have helped broaden our understanding of the mechanisms by which DNA glycosylases locate and excise chemically modified DNA nucleobases.

    

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4. Development of Cu 2+ -Based Distance Methods and Force Field Parameters for the Determination of PNA Conformations and Dynamics by EPR and MD Simulations

   https://doi.org/10.1021/acs.jpcb.0c05509  

   Gamble Jarvi, Austin ; Sargun, Artur ; Bogetti, Xiaowei ; Wang, Junmei ; Achim, Catalina ; Saxena, Sunil ( August 2020 , The Journal of Physical Chemistry B)

   Peptide nucleic acids (PNAs) are a promising group of synthetic analogues of DNA and RNA that offer several distinct advantages over the naturally occurring nucleic acids for applications in biosensing, drug delivery, and nanoelectronics. Because of its structural differences from DNA/RNA, methods to analyze and assess the structure, conformations, and dynamics are needed. In this work, we develop synergistic techniques for the study of the PNA conformation. We use CuQ2, a Cu(II) complex with 8-hydroxyquinoline (HQ), as an alternative base pair and as a spin label in electron paramagnetic resonance (EPR) distance methods. We use molecular dynamics (MD) simulations with newly developed force field parameters for the spin labels to interpret the distance constraints determined by EPR. We complement these methods by UV–vis and circular dichroism measurements and assess the efficacy of the Cu(II) label on a PNA duplex whose backbone is based on aminoethylglycine and a duplex with a hydroxymethyl backbone modification. We show that the Cu(II) label functions efficiently within the standard PNA and the hydroxymethyl-modified PNA and that the MD parameters may be used to accurately reproduce our EPR findings. Through the combination of EPR and MD, we gain new insights into the PNA structure and conformations as well as into the mechanism of orientational selectivity in Cu(II) EPR at X-band. These results present for the first time a rigid Cu(II) spin label used for EPR distance measurements in PNA and the accompanying MD force fields for the spin label. Our studies also reveal that the spin labels have a low impact on the structure of the PNA duplexes. The combined MD and EPR approach represents an important new tool for the characterization of the PNA duplex structure and provides valuable information to aid in the rational application of PNA at large. 

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5. Thionated organic compounds as emerging heavy-atom-free photodynamic therapy agents

   https://doi.org/10.1039/d0sc04747c  

   Ortiz-Rodríguez, Luis A. ; Crespo-Hernández, Carlos E. ( October 2020 , Chemical Science)

   null (Ed.)

   This minireview focuses on recent progress in developing heavy-atom-free photosensitizers based on the thionation of nucleic acid derivatives and other biocompatible organic compounds for prospective applications in photodynamic therapy. Particular attention is given to the use of thionated nucleobase derivatives as “ one-two punch ” photodynamic agents. These versatile photosensitizers can act as “ Trojan horses ” upon metabolization into DNA and exposure to activating light. Their incorporation into cellular DNA increases their selectivity and photodynamic efficacy against highly proliferating skin cancer tumor cells, while simultaneously enabling the use of low irradiation doses both in the presence and in the absence of molecular oxygen. Also reviewed are their primary photochemical reactions, modes of action, and photosensitization mechanisms. New developments of emerging thionated organic photosensitizers absorbing visible and near-infrared radiation are highlighted. Future research directions, as well as, other prospective applications of heavy-atom-free, thionated photosensitizers are discussed. 

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