Artificial Nucleotides Developed for the First Time Could Pave the Way to Fully Synthetic Nucleic Acids With Enhanced Chemical Functionalities

For billions of years, the history of life on Earth has been written with only four letters: A, T, C, and G. DNA, the hereditary material that carries the genetic information in all living organisms, is made up of organic molecules known as nucleotides. Over the recent years, scientists have contemplated the possibility of expanding the genetic alphabet by generating new nucleotides with additional properties.

Structure of Nucleotides

Nucleotides are the basic structural units for nucleic acids such as DNA and RNA. Every nucleotide is composed of five-sided sugar, phosphate group, and nitrogenous base.

There are four different nitrogenous bases which include adenine (A), thymine (T), cytosine (C ), and guanine (G). These letters represent the code for the amino acids which make up proteins. The nitrogenous bases bind the two strands of DNA together, with adenine always bonding to thymine on the opposite side, and cytosine and guanine doing likewise.

The bases are found in the middle of the DNA double helix, while sugar and phosphate group make up the backbone. This backbone is held together by the chemical bond between the phosphate group of one nucleotide and the sugar of the neighboring nucleotide. Meanwhile, the hydrogen bonds between the bases across from one another hold the two strands of the double helix together.

Artificial Building Blocks of Life

For the first time, experts from the University of Cologne (UoC) have shown that the structure of nucleotides can be modified to a great extent in the laboratory. This led to the development of artificial nucleotides with several additional properties.

Led by Hannah Depmeier, the research team created the threofuranosyl nucleic acids which contain new, additional base pairs. The details of their study are discussed in the paper "Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage".

This research offers the first steps on the way to fully artificial nucleic acids which can be useful for therapeutic purposes. Artificial nucleic acids differ from their original counterparts in terms of structure. These changes affect their stability and function as organic molecules.

According to the researchers, their threofuranosyl nucleic acid is more stable than the natural nucleic acids. This is because the 5-carbon sugar deoxyribose was replaced by a 4-carbon sugar, and the number of nucleobases increased from four to six. By exchanging the sugar, the threofuranosyl nucleic acid is not recognized by the degradation enzymes of the cell.

This has been a challenge for therapeutics based on nucleic acids, as synthetically produced RNA introduced into a cell rapidly degrades and loses its effects. With the introduction of TNAs into cells that remain undetected, the therapeutic effects can be maintained for longer.

Additionally, the built-in artificial base pair allows alternative binding options to target molecules in the cell. This function can be used in developing new aptamers, or short DNA or RNA sequences. Aptamers can be useful for the targeted control of cellular mechanisms.

The newly-developed threofuranosyl nucleic acid can be beneficial in the targeted transport of drugs to particular organs in the body. Aside from this, the artificial nucleic acid can also help recognize viral proteins or biomarkers.