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New Nucleic Acid Analogs: A Potential “Medicine for Genes”
Biology

New Nucleic Acid Analogs: A Potential “Medicine for Genes”

Novosibirsk researchers (Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences) were fortunate (a rare luck in the scientific world) to discover a new class of nucleic acid analogs tat are absent in the natural world, which can be the core of efficient gene-targeted drugs

Because of their ability to form complementary complexes with nucleic acids, phosphoryl guanidine oligonucleotides…Stop there! Most likely, this phrase would be just gibberish for a broad audience (much to the regret of molecular biologists). Moreover, I recently spoke on occasion with an aspiring science journalist, who answered to the question whether he knew how DNA worked, which was the topic of his, sort of accusingly if not proudly, “Of course, no! But I am a journalist, not a biologist!”

However, to understand and appreciate the discovery of Novosibirsk researchers, we need to have elementary knowledge about the structure of this most amazing molecule (those who know may skip the next two paragraphs; besides, Yandex gives “exactly” one million answers to the question on how DNA works). Avoiding excess details, the issue boils down to the following.

The nucleic acids, be it DNA or RNA (the difference between them is nonessential in our case), are a long chain of identical “beads” (sugar residues) joined together via phosphate groups, –OPO–. Special compounds, nitrogenous bases of four types (A, T, G, and C), “are suspended” to this chain as ball pendants to a bracelet. Pairs of these bases “hand in hand” (or in a key–lock manner) keep two DNA strands together. Note that any random bonds are strictly prohibited: the pairs are always formed of the same bases, namely, A–T or G–C. The famous DNA helix, composed of two “mirrored” strands is formed thanks to this property, referred to as complementarity.

The second thing we have to know is what the gene is. In the most simplified variant, this is a short region of the DNA molecule, which “encodes” the structure of another most important class of biological polymers, i.e., proteins. Triads of the successively arranged nucleotide beads act as letters of the genetic code: one triplet encodes one amino acid. When one of our genes starts its “work,” the DNA helix unwinds and a new, intermediary, nucleic acid is constructed on it (also according to the complementarity principle); it is referred to as RNA and further acts as a template for protein synthesis.

The DNA structure was identified in 1953; and it took another decade to decipher the genetic code. As early as in 1967, N.I. Grineva, a young scientist with the Institute of Organic Chemistry, Siberian Branch, USSR Academy of Sciences, proposed the idea, genial in its simplicity, of a targeted impact on genes utilizing the ancient Roman principle Similia similibus curantur (like is cured by like). The proposed “tool” was relatively short fragments of nucleic acids (oligonucleotides) able to complementarily bind to certain regions of nucleic acids in cells.

The implementation of this idea would make it possible to create an ideal medicine with precisely targeted action, since any gene, be it a bacterial DNA or an oncogene, predisposing cells to develop into a cancer, has its own unique sequence of “letters” of the genetic code. Thus, it is possible to synthesize an oligonucleotide than can read a “piece of phrase” only of the target DNA fragment and not of any other sequence. Then, if this oligonucleotide is supplied with a chemical group able to interact with the target nucleic acid (e.g., to destroy it), we get a highly specific drug, such as a precision-guided munition.

However, there is a long and winding road leads from a theory, no matter how brilliant it is, to its practical application. The idea of gene-targeted oligonucleotide drugs was no exception despite considerable advance in the elapsed half century—a living cell is too complex a system, which interferes with repeating at a cellular level the achievements obtained in a laboratory tube.

The search for the chemical modifications of nucleic acids that would allow for more efficient implementation of the functions assigned to them—to enter the cell through its lipid membrane, to resist the attacks of cell enzymes attempting to destroy “alien” DNA, and, finally, to recognize the DNA target and tightly bind to it—is among the topical research areas. Here we finally approach the discovery of phosphoryl guanidines, which was made by direct successors to the research of Novosibirsk biochemists of the last century.

In these new compounds, one oxygen atom within the negatively charged phosphate groups, linking the adjacent nucleotides, is replaced with a rather “bulky” phosphoryl guanidine group, making these “bridges” electrically neutral. Such a modification gives many useful properties to these new compounds.

It turned out that the introduction of a single phosphoryl guanidine group into an oligonucleotide is sufficient to delay its cleavage in the cell for over an hour, whereas cell enzymes completely destroy a common oligonucleotide in less than five minutes. However, the point is that despite a considerable size of these supplements, phosphoryl guanidine oligonucleotides form complementary complexes with the target DNA that do not differ in their stability from the natural double-stranded helix. These new compounds are readily soluble in water; moreover, their electric neutrality theoretically enhances their penetration through a negatively charged surface of the cell lipid membranes.

Moreover, such oligonucleotides can combine charged and neutral regions of different lengths, while the oxygen atoms in phosphate group remaining “free” of substitute can be replaced with some other useful chemical groups. This approach opens new prospects for creating oligonucleotides with manifold diverse properties and “skills.” Biological activities of the first representatives of a vast class of phosphoryl guanidine derivatives of nucleic acids is now intensively studied, and the discoverers expect that in future, these preparations will be able to challenge several most severe maladies, from viral and bacterial infections to autoimmune and cancer diseases.

The new concept for constructing therapeutic oligonucleotides is referred to as NONA (nonuniformly charged oligonucleotide analogs). This name was chosen not by chance: as is known Nona was the older sister of Parcae, female personifications of destiny, and she span the thread of life, so similar to the thread-like DNA molecule…

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