Telomerase inhibitor: details

Chemists have suppressed the critical mechanism of cellular immortality

Alice Bakhareva, N+1

A group of scientists from Australia and the USA has synthesized a molecule that covalently and irreversibly binds to cancer cell telomerases and inhibits them. As a result, the viability of tumor cells decreased, and the work of normal components was not affected. The researchers were inspired to create a new substance by the natural antibiotic chromactomycin, which is produced by bacteria. The article has been published in the journal of the American Chemical Society Chemical Biology.

Telomeres are areas at the ends of chromosomes that consist of numerous repeats of a certain sequence of several nucleotides. They are necessary for the protection of chromosomes, but the mechanism of DNA replication is designed so that telomeres are slightly reduced with each division. If the end sections reach a critical length, the DNA is damaged and the cell triggers protective mechanisms: it stops dividing and activates apoptosis (programmed death) or aging.

There are cells that are able to lengthen telomeres on their chromosomes and thereby divide more times. These are stem, embryonic and primary germ cells. The protein that completes the end sections of DNA is called telomerase, for its research in 2009 was awarded The Nobel Prize in Physiology or Medicine.

Telomerase (blue) completes telomeres (black) using an RNA matrix (red). Here and further drawings from the article in ACS Chemical Biology.

In somatic cells, the work of telomerase is suppressed, but this protein is present in the active state in 90 percent of cancer cells. It is believed that it allows tumors to divide indefinitely and bypass the mechanisms of cell death. In addition to the fact that telomerase lengthens the end sections of chromosomes, it participates in other processes that are associated with the development of cancer.

The search for a way to suppress telomerase activity is one of the directions in the fight against cancer. A group of scientists led by Rick Betori from Northwestern University drew attention to a natural telomerase inhibitor - chromactomycin. It is an antibiotic isolated from a strain of Streptomyces bacteria. The task of the researchers was to create a substance that would also interact with telomerase, but could be easily synthesized in the laboratory.

Hrolactomycin.

With the help of computer modeling, researchers have developed more than a thousand simplified analogues of hrolactomycin (they were called "chronologists") – molecules whose properties, according to calculations, are similar to the properties of the original substance. 330 of them selected the most suitable models and analyzed their interaction with telomerase by molecular docking (a technology that allows you to visualize the interaction of two macromolecules and predict its stability).

Then 150 compounds were synthesized and their properties were analyzed. The best substances were tested on cell extract and live human cancer cells that belonged to tumors of various natures. To make sure that the molecules do not interact with other components of the cell, we checked their effect on cancer cells that do not have telomerase, and the reaction with cysteine.

The most suitable sample was NU-1, which was synthesized in 4 stages. It covalently and irreversibly bound to telomerase (due to the interaction of the exomethylene group with the cysteine site of the protein) and effectively inhibited it. NU-1 also reduced the viability of cancer cells. The substance had a negligible effect on cells in which telomerase is absent, and low reactivity with cysteine.

NU-1.

Telomerase activity in cell extract (left) and whole cancer cells (right). The horizontal axis is the logarithmic concentration of NU-1.

Survival of cancer cells of various lines. Burgundy and orange indicate cells in which there is no telomerase, their viability has not decreased. The horizontal axis is the logarithmic concentration of NU-1.

The substance synthesized in this work inhibits telomerase more effectively than the results of other developments. It is necessary to work on creating even more effective molecules and test them not only on human cell cultures, but also on animal models.

The knowledge of its detailed structure, which was studied in 2018 using the cryoelectronic microscopy method, helped to model the interactions of synthetic substances with telomerase.

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