Efficient DNA Condensation by a C₃‐Symmetric Codeine Scaffold

Abstract

A novel tripodal codeine scaffold (CC3) was rationally designed using computational methods as a DNA condensing alkaloid. Separation of the piperidine nitrogen atoms in CC3 is considerably larger at 14.36 Å than previously reported tripodal opioids allowing for enhanced aggregation of larger DNA plasmids (>4,000 bp). The scaffold undergoes protonation at physiological pH that allows for controlled compaction and release of nucleic acids. Condensation is inhibited under basic conditions and nucleic acid release can be achieved by modulating the ionic strength. Zeta potential experiments indicate stabilised DNA particles at low alkaloid loading with AFM measurements showing particles sizes with a height of 103 nm and diameter of 350 nm. Since condensation is a prerequisite for the cellular uptake of DNA, this new class of alkaloid represents a novel nucleic acid condensation agent with potential gene therapy applications.

A Click Chemistry‐Based Artificial Metallo‐Nuclease

“…Chemie plex, this is the first observation that Cu II -TC-Thio shares similarities with DNA condensing C 3 -symmetric opioidbased agents. [17] Finally, to help confirm the nature of the Cu II -TC-Thio DNA binding mode, preassociative molecular docking studies with the Dickerson-Drew dodecamer (DDD; PDB code: 1BNA) were undertaken. Here, 1BNA was treated as a rigid oligomer and the starting position of the complex was randomised to minimise starting position bias (see Supporting Information S1.10 for full details).…”

A Click Chemistry‐Based Artificial Metallo‐Nuclease

“…While this condensation behaviour may, to some extent, be expected for a trinuclear transition metal com- plex, this is the first observation that Cu II -TC-Thio shares similarities with DNA condensing C 3 -symmetric opioidbased agents. [17] Finally, to help confirm the nature of the Cu II -TC-Thio DNA binding mode, preassociative molecular docking studies with the Dickerson-Drew dodecamer (DDD; PDB code: 1BNA) were undertaken. Here, 1BNA was treated as a rigid oligomer and the starting position of the complex was randomised to minimise starting position bias (see Supporting Information S1.10 for full details).…”

Artificial Nucleobase-Directed Programmable Synthesis and Assembly of Amphiphilic Nucleic Acids as an All-in-One Platform for Cation-Free siRNA Delivery

“…Introducing exogenous nucleic acids into targeted cells to counteract defective gene(s) is rapidly becoming an attractive method of treating various diseases. − In contrast to conventional therapies, this genetic manipulation technology, such as RNAi and CRISPR, can, in principle, target any gene of interest, including the undruggable, with high potency and specificity, thus offering durable and possible curative therapeutic benefits. − However, the intrinsically poor nuclease tolerance and transmembrane transport of nucleic acids have long been the major hurdles in their clinical translation. , Therefore, extensive efforts have been devoted to developing nonviral carriers for improved genetic delivery. − , Despite sustained formulation advances over decades and enhanced transfection, these cationic carriers can frequently trigger adverse systemic effects. , As such, balancing the trade-off between effectiveness and toxicity of formulations remains incredibly challenging for the delivery and biomedical applications of nucleic acid therapeutics.…”