In an article published in the journal Chemistry & Biology, researchers describe a new mechanism that inhibits the activity of proteasomes, protein complexes that are a target for cancer therapy
A new mechanism to inhibit proteasomes, protein complexes that are a target for cancer therapy, is the topic of an article published in the journal Chemistry & Biology. The first author of the study is Daniela Trivella, researcher at the Brazilian Biosciences National Laboratory at the Brazilian Center for Research in Energy and Materials (LNBio/CNPEM).
The findings of the study, conducted with FAPESP support in partnership with researchers from the University of California in San Diego, United States, and at the Technische Universität München, in Germany, are paving the way for the development of a new generation of chemotherapy drugs that are more effective and less toxic.
"We have already developed a series of molecules based on the newly identified mechanism. Now we plan to synthesize them in partnership with CNPEM researcher Marjorie Bruder and test their potential. The goal is to optimize the proteasome inhibition effect, make the compound even more selective of tumor cells and eliminate the resistance problems found with drugs that are currently available on the market," Trivella said.
A member of the category of enzymes known as proteases, the proteasome is a protein complex responsible for several essential functions inside cells, such as eliminating harmful or non-functioning proteins and regulating the processes of apoptosis (programmed cell death), cell division and proliferation.
In 2012, the drug carfilzomib, inspired by a natural molecule called epoxomicin, was approved. Also in 2012, U.S. and Brazilian researchers isolated a natural molecule in cyanobacteria from the Caribbean called carmaphycin, whose reactive group (the portion of the molecule that interacts with the proteasome) is the same as that of carfilzomib. The molecule is known as an epoxyketone.
"Epoxyketones are very potent selective inhibitors of the proteasome because they interact with this enzyme in two stages: the first reversible and the second irreversible," Trivella explained.
To optimize its effect and find new reactive groups, researchers from the Scripps Institution of Oceanography at the University of California in San Diego developed a series of synthetic analogs with slight structural modifications.
Trivella tested these compounds during an internship in California in her post-doctoral research when she was still associated with the Chemistry Institute at the University of Campinas (Unicamp).
One of the molecules tested had an enone as a reactive group and had characteristics of carmaphycin and another natural molecule named syringolin, isolated from plant pathogens.
By investigating the reaction mechanisms of the new molecule, named carmaphycin-syringolin enone, the researcher verified that unlike syringolin, and thus like the epoxyketone, the enone interacts with the proteasome in two stages, with the second stage being irreversible.
Additionally, Trivella had observed that in the case of the enone, the second reaction occurs more slowly, increasing the duration of the reversible phase of carmaphycin-syringolin enone inhibition.
"Because the irreversible inactivation of the proteasome has toxic effects, the best window of reversibility observed for the carmaphycin-syringolin enone will potentially reduce the toxicity of this new class of proteasome inhibitors," Trivella said. "The compound would therefore present a balance between selectivity and potency."
Toxicity tests are still underway. In parallel, studies have been conducted with the help of crystallography techniques to discover exactly how the interaction between the enzyme target and the carmaphycin- syringolin enone target occurs.
"We discovered that a chemical reaction called hydroamination occurs, which had never before seen under physiological conditions. This type of reaction is frequently used by synthetic chemists in preparing substances, but normally it requires very specific temperature and pH conditions and the use of catalysts to occur. It has never been reported as a mechanism of enzyme inhibition," Trivella said.
Inspired by this new mechanism for proteasome inhibition, the LNBio group plans to synthesize and test a new series of carmaphycin-syringolin enone analogs to determine their effects on the therapeutic window (preferential death of tumor cells in relation to healthy cells) and assess whether they are also capable of reacting with proteasomes that are resistant to traditional inhibitors.
Another of Trivella's goals is to look for natural compounds in Brazilian biodiversity that could serve as inspiration for the design of other categories of proteasome inhibitors.
Samuel Antenor | Eurek Alert!
A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau
On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...
16.08.2017 | Event News
04.08.2017 | Event News
26.07.2017 | Event News
18.08.2017 | Life Sciences
18.08.2017 | Physics and Astronomy
18.08.2017 | Materials Sciences