Chemical researchers at Scripps Research, Hans Renata and Alexander Adibekian, They have discovered a way to efficiently create a synthetic version of a valuable natural compound called cepafungin I, which has shown promise as an anticancer agent.
This bacterial secretion can block a piece of molecular machinery known as proteasome, a strategy that many existing anticancer drugs use to destroy tumor cells. The point is that cepafungin I binds to not one but two sites on the proteasome, offering much more promising results.
The complex molecular structure of cepafungin
The cepafungin I It first intrigued researchers for its usefulness as an antifungal substance and then as a promising anticancer agent. It kills cells by acting on the proteasome, which is responsible for cleaning the 'garbage' produced by cells. When the function of the proteasome is blocked, cells are affected by its waste and die. As explained Hans Renata:
Because cepafungin I is able to engage the proteasome in two ways, it allows amplification of its effect. We demonstrate that this compound elicits many downstream biological responses similar to those of the FDA-approved chemotherapy bortezomib, while also having certain qualities that may translate into fewer unwanted side effects for patients.
Due to the complex molecular structure of cepafungin, however, manufacturing enough of it efficiently is a challenge. The Scripps research team has done it and can synthesize the compound in just nine steps. For comparison, a related compound known as glidobactin A was synthesized in 21 steps in 1992, which was considered a milestone at the time.
The team was able to speed up the process by using certain enzymes that allowed the construction of one of the key building blocks of the compound, an amino acid. They then developed other methods to simplify the construction of other parts of the molecule, including a portion of branched lipids that were later found to contributed to the potent activity of the compound.
After creating the compound, chemists discovered that, in addition to being exceptionally selective in targeting two sites on the proteasome, it did not show any unwanted cross-reactions with other proteins in cells, a characteristic that could make it a better drug candidate.
The FDA has already approved three proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) for the treatment of multiple myeloma. "But those drugs have some potentially serious side effects and cancer cells can develop resistance to them over time," says co-author Adibekian, an associate professor of chemistry at Scripps Research. 'There is a need for alternative and more specific proteasome inhibitors.'
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The news
It is possible to efficiently create the synthetic version of a very promising compound as an anti-cancer agent
was originally published in
Xataka Science
by
Sergio Parra
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