Chemists build natural anti-cancer compound with lean new process

Date:
August 6, 2020
Source:
Scripps Research Institute
Summary:
Creative chemists employ enzymes to build a complex but promising
natural anti-cancer agent called cepafungin I in a lean nine steps.



FULL STORY ========================================================================== Scripps Research chemists Hans Renata, PhD, and Alexander Adibekian,
PhD, have discovered a way to efficiently create a synthetic version of
a valuable natural compound called cepafungin I, which has shown promise
as an anti-cancer agent.


========================================================================== Through this, they were able to understand how the bacterial secretion
is able to block a piece of molecular machinery known as a proteasome --
a strategy that many existing cancer medications use to destroy tumor
cells. They found that cepafungin I bound to not one but two places on
the proteasome, enacting a powerful result. Their report appears in the
journal Cell Chemical Biology.

"Because cepafungin I is able to engage the proteasome in two ways, it
allows for amplification of its effect," Renata says. "We showed that
this compound elicits many similar downstream biological responses as the FDA-approved chemotherapy bortezomib, while also having certain qualities
that may translate into fewer unwanted side effects for patients."
Recreating nature Cepafungin I first intrigued researchers because of
its usefulness as an antifungal substance, and later as a promising
anti-cancer agent. It kills cells by acting on the proteasome, which is responsible for clearing away the "garbage" produced by cells. When the proteasome's function is blocked, cells are overcome with their waste
and die.

But making enough of the compound to be able to study its activity or
enable its eventual use a medication has proven challenging, due largely
to its complex molecular structure. In the field of chemistry, scientists
seek to create the desired structure in as few steps as possible, which
leads to cost and time savings. But with complex compounds, that isn't
an easy task.



==========================================================================
The Scripps Research team was able to overcome these challenges and
synthesize the compound in just nine steps. For comparison, a related
compound known as glidobactin A was synthesized in 21 steps in 1992 --
and that was considered a landmark at the time.

The team was able to speed up the process by using certain enzymes that
enabled construction of one of the compound's key building blocks,
an amino acid. Then they developed other creative chemistry methods
to simplify construction of other parts of the molecule, including a
branched lipid portion that was subsequently found to contribute to the compound's potent activity.

"Our approach saved us many steps in synthesizing the final compound
compared with using classical chemical approaches," says Alexander
Amatuni, a graduate student at Scripps Research.

A good sign for safety After creating the compound, the chemists
discovered that in addition to being exceptionally selective at targeting
two sites on the proteasome, it didn't show any undesired cross-reaction
with other proteins in cells, a feature that could make it a better
drug candidate.



========================================================================== Three proteasome inhibitors -- bortezomib, carfilzomib and ixazomib --
have already been approved by the U.S. Food and Drug Administration
for the treatment of multiple myeloma. "But those medications have some potentially serious side effects, and cancer cells may develop resistance
to them over time," says co-author Adibekian, associate professor of
chemistry at Scripps Research. "There is a need for alternative, more
specific proteasome inhibitors." Graduate student Anton Shuster noted
that the team's discoveries were made possible by a close collaboration
of labs with different expertise "By combining the two complementary technological platforms -- chemoenzymatic synthesis from the Renata lab
and chemoproteomics from the Adibekian lab -- we were able to succeed,"
Shuster says. "Having the opportunity to work with scientists with
divergent research background is what makes working at Scripps Research particularly exciting." Going forward, the scientists plan to continue structure-guided design of similar molecules with alternative structural features in search of useful compounds with superior anti-cancer activity.

The methods they developed will enable them to change various parts of
the structure with relative ease, Amatuni says, allowing for further investigation of biological activity. "The emphasis on translational
research at Scripps Research enables this discovery," Adibekian
says. "We're excited about developing the molecule further."

========================================================================== Story Source: Materials provided by Scripps_Research_Institute. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Alexander Amatuni, Anton Shuster, Alexander Adibekian, Hans Renata.

Concise Chemoenzymatic Total Synthesis and Identification of
Cellular Targets of Cepafungin I. Cell Chemical Biology, 2020;
DOI: 10.1016/ j.chembiol.2020.07.012 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/08/200806153540.htm

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