Recently, researcher Fu Leilei and her team at Southwest Jiaotong University have developed a novel small molecule agonist targeting SIRT3 and successfully applied it to treat heart failure.
At the same time, the candidate small molecule drug targeting SIRT3 is a homocamptothecin derivative, 2-APQC.
Through this, the team not only deeply elucidated the important function of SIRT3 in the treatment of heart failure, but also found that the novel SIRT3-targeting small molecule agonist 2-APQC has good prospects for drug development.
That is, 2-APQC can not only regulate the classic pathways for improving heart failure mediated by SIRT3, but also affect mitochondrial proline metabolism and reactive oxygen species metabolism by regulating the SIRT3-PYCR1 pathway, thereby maintaining the mitochondria in a stable state.
At the same time, this study also highlights the important significance of SIRT3 regulation of mitochondrial amino acid metabolism for heart failure.The derivative of camptothecin, 2-APQC, not only has the potential to be developed as a new targeted small molecule drug for treating heart failure by targeting SIRT3, but it is also very promising for the development of heart-protective health products.
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At present, the team is continuing to explore and looks forward to the results being presented to everyone in the form of products as soon as possible.
"Longevity Gene" SIRT3
It is reported that SIRT3 is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase, known as the "longevity gene," and is also a very fascinating druggable target.
For the target of SIRT3, the team has conducted in-depth research for nearly 10 years, through which it has been found that SIRT3 can truly achieve the function of "small modification, big effect."Additionally, SIRT3 plays a "corrective" role in the regulation of substrates, particularly in deacetylation control.
This gives SIRT3 a certain selectivity, that is, it can selectively correct the pathological state of diseases while having minimal impact on normal states.
Based on the unique charm of SIRT3, the research group has developed small molecule modulators that can target SIRT3, which are expected to be used in the treatment of diseases such as cancer, neurodegenerative diseases, and heart failure.
At the same time, they found that SIRT3 may play an important role in the improvement of heart disease.
As we all know, chronic heart failure is an important threat to human health. And the commonly used heart failure treatment drugs are often only aimed at treating the symptoms of the disease.This is similar to urging already weakened heart cells to alleviate symptoms by working harder, without truly addressing the improvement of myocardial cell function. In the long run, the patient's heart function does not see an essential improvement.
In the long term, improving the function of myocardial cells is a wiser strategy for the prevention and treatment of heart failure.
Previously, the team mainly focused on the role of SIRT3 in cancer and the discovery of small molecule candidate drugs.
Initially, Fu Leilei did not intend to study the potential of SIRT3 in other diseases.
While designing SIRT3-specific targeting agonists, she targeted the structural differences of SIRTs and, based on the deacetylation process of SIRT3, discovered two active pockets.By adjusting these two pockets, it is possible to accelerate the deacetylation process of SIRT3.
Later, Fu Leilei found that when designing and screening drugs for these two pockets respectively, some compounds showed good SIRT3 agonist activity, but they had almost no killing effect on tumors.
This made the whole team quite frustrated for a while, and the project was suspended for a period of time. Later, in a communication, Fu Leilei discussed this issue with Dr. Peng Fu from Sichuan University.
Some of Peng Fu's suggestions were very beneficial to Fu Leilei's research group, such as Peng Fu's proposal to look at the problem from a dialectical perspective?
That is, SIRT3 agonists may be suitable for all diseases caused by impaired SIRT3 function or insufficient SIRT3."In other words, I have always been confined within my own thinking. Later, through systematic bioinformatics analysis combined with clinical big data, we found that SIRT3 agonists may have more potential in heart failure, which also prompted the establishment of this topic," said Fu Leilei.
After establishing this topic, Fu Leilei's team began a systematic study. To discover the camptothecin derivative analog 2-APQC, they spent about a year.
During this period, the research group screened a large number of small molecule compounds and conducted preliminary activity tests, finally determining 2-APQC as the optimal candidate.
However, Fu Leilei encountered a new problem: since 2-APQC was originally synthesized from a small molecule library, and she wanted to fully verify the effect and mechanism of action of 2-APQC, this required a large amount of small molecule compounds.
In the history of drug research, scientists also encountered similar problems in their pharmacological research on paclitaxel. Due to insufficient quantity, it was impossible to carry out related experiments.At this time, Fuleilei collaborated with Peng Fu, and later two of Fuleilei's graduate students spent half a year to obtain 100g of the hard-won pure 2-APQC.
These "light as a feather" yet "heavy as a mountain" small molecules allowed everyone to "squander" temporarily and carry out experiments.
Subsequently, they initiated a comprehensive evaluation of the efficacy and study of the mechanism of action. When analyzing the experimental data, Fuleilei timely adjusted the research focus according to the experimental results.
Ultimately, they discovered the significance of proline metabolism regulated by SIRT3 for heart failure and fully elucidated the efficacy and mechanism of action of 2-APQC.
Recently, the related paper was published in Signal Transduction and Targeted Therapy (IF 39.3) with the title "2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis."Dr. Peng Fu from the School of Pharmacy at Sichuan University is the first author, and Fu Leilei serves as the corresponding author.
A Hand-drawn "Rat-Raising Manual" by a First-Year Female Graduate Student
Despite the paper having been published, there is one thing that Fu Leilei remembers very vividly. Since this project involved the breeding work of transgenic mice, Fu Leilei assigned it to a first-year female graduate student in the team.
This task has a relatively long work cycle and is also quite monotonous, and Fu Leilei personally did not pay much attention to it.It wasn't until after a group meeting that the girl handed over a "Rat-Raising Manual" to Fu Leilei. Upon seeing it, Fu Leilei was extremely touched and gratified.
"Such a tedious task, yet she documented it in great detail. The manual is well-illustrated, with hand-drawn sketches of the rats' conditions and photographs of them, truly making one feel that she treats and pays attention to each rat as if they were a little baby," said Fu Leilei.
From this small incident, she also sensed the youth and enthusiasm of young students, and once again realized that there are no trivial matters in experiments and that attitude determines everything.
Fu Leilei has kept this "treasure" and uses it as a reminder that there are no unimportant small tasks in her work.
It is precisely every seemingly insignificant detail that determines the level of work. Fu Leilei said, "I also constantly encourage myself to maintain my passion and keep striving!"Of course, the current research is still immature, and the models used are relatively singular, and cannot fully reflect the clinical situation of heart failure patients at present.
Fu Leilei is also thinking and improving. In general, this work may only be the prelude of the research group's research on SIRT3 heart failure.
Next, they will carry out a comprehensive optimization of 2-APQC, designing and synthesizing better small molecule SIRT3 target agonists from the perspective of medicinal chemistry.
Looking at the current results, the agonistic ability of 2-APQC to SIRT3 is comparable to that of andrographolide, and there is still a lot of room for optimization and improvement. They are also carrying out this work and believe that the research results will be available to everyone soon.
In addition, Fu Leilei is studying whether a new delivery system can be used to deliver 2-APQC.Currently, she is also considering the intelligent delivery of 2-APQC by detecting the level of proline in myocardial cells through the use of smart microneedles, with the hope of achieving more accurate and safer therapeutic effects.
