Interview with Liang Xingguo, China Haida team breaks traditional cognition, enabling any sequence DNA under certain conditions to form a left-handed double helix, plan development related drugs2022-01-25 06:02:57 52 ℃
It is well known that DNA is a double-stranded structure, and in the ionic strength and humidity environment of different solutions, it has different types, such as the right-handed A-DNA, B-DNA, and left-handed Z-DNA.
Figure 丨 Different types of DNA (Source: Molecular Biology)
Previously, only the sequence of D (Cg) N, CG) N, APPs was generally formed to form left spiral DNA (Z-DNA) under special conditions such as high salt concentration, chemical modification or strong negative overshina. Scientists have a variety of speculations for ordinary DNA sequences that form z-DNA, but there is no direct technical means to study. At the same time, everyone has lacks sufficient understanding for the essence of Z-DNA in the body APP sequence.
Recently, the Professor of Liang Xingguo, a School of Food Science and Engineering, China, published a research papers titled "Nonalternating Purine Pyrimidine Sequences Can Form Stable Left-Handed Dna Duplex By Strong Topology".
Taking this, Synbio invited Professor Liang Xingguo to share his research results.
Liang Xingguo graduated from the Department of Chemical Engineering, Tianjin University, was graduated from Tianjin University Chemical Engineering. In 1995, he received a master's degree in professionalism. He was mainly engaged in organic pigments and its dispersant synthesis, nano-scattered Research on ink printer ink.
In 1999, he went to the University of Engineering University, the University of Engineering, the University of Engineering. This is the first time that Liang Xingguo has exposed to biochemistry, but he only won a doctorate in two and a half. During the post-post, the Tutor Chi Hohan Leizhi was studying DNA chemical shear. In less than half a year, I found a breakthrough of key issues, namely DNA-specific shear utilizing the difference between single-stranded and double-stranded DNA. cut. In 2003, the University of Boston was studied by Nucleic acid testing.
In 2011, I was now professor of the China Ocean University Food and Engineering College, the main research direction is the nucleic acid chemistry, the qualitative quantitative detection of nucleic acid in food, and the nutrients in the metabolic process.
丨 梁 兴 国 (Source: Visitors)
From Liang Xingguo's resume, we can see many transformation research directions, and have achieved proud results in every direction. "The creation of the times and the love of their own research have prompted me to choose biochemistry." Liang Xingguo said.
Any sequence will form a stable Z-DNA
Studies have shown that Z-DNA is associated with gene expression regulation, genetic instability, and a variety of human diseases, such as Z-DNA forming sequences may increase the frequency of recombinant, deletions and translocation events in the cellular system.
However, Z-DNA is easily converted into thermodynamically advantageous B-DNA, and the B-DNA is stabilized under normal conditions, and Z-DNA can only be at high salt concentrations or certain special chemical molecules (such as specific chiral molecules or Antibody) can be formed under special conditions such as induction, so it is extremely difficult to obtain a stable Z-DNA under physiological conditions, which has greatly restricted the research on Z-DNA functional characteristics and mechanisms. Development of related fields.
In fact, in the 1970s, scientists represented by Alexander Rich (MIT biophysics) found and confirmed the existence of Z-DNA, but due to difficult research, the scientific community Z - DNA features a lack of adequate understanding.
After Liang Xingguo returned to China, he was committed to preparing a stable Z-DNA. In the past five years, the team of Liang Xingguo has achieved significant breakthroughs in Z-DNA in DNA and RNA, and constructing physiological conditions.
In 2019, its team studied the method of forming a stable Z-DNA under normal physiological conditions, simply inducing the topology limit of two complementary non-chemically modified single-stranded DNA small rings, will be spontaneously induced. Double-stranded DNA is wound into a stable Z-DNA. Just as the two annular rubbles are entangled, the left spiral and right screw will be formed simultaneously. Studies have shown that the use of this method even if the random sequence that is not possible to form Z-DNA can also form Z-DNA. This results were published in JACS in March 2019.
The article published in NAR is more traditional, "only the APP sequence can form Z-DNA under strong topology restrictions", through various biochemical methods, discovery, in the topology limit, ordinary sequence forms the same APP sequence This particular sequence is also az-DNA.
Liang Xingguo said, "The complementary DNA sequence can form two states of Z-DNA and B-DNA, while the free energy is very different between the two states." He added Road, "The reason why the APP sequence in the body is prioritized is that the free energy of the left spiral and right spiral of the APP sequence is more close to the non-APP sequence, just like water mainly tends to low. Like the flow, molecules are also foremostly present in a lower state. In a region without APP sequence, non-APP sequences will have a relatively stable Z-DNA structure under appropriate topology limits. "
Screening of Z-DNA schematic and the same sequence of linear SSDNA, Z-DNA and B-DNA free energy levels (Source: Research papers)
Plan to develop Z-DNA related drugs
"From the perspective of drug development, it is no longer limited to" CGCGCG "such as the corresponding sequence as needed. At present, some diseases such as lupus erythematosus are related to Z-DNA or Z-DNA antibodies, in depth to Z-DNA It is important to understand the mechanism of understanding the role of disease and development related drugs. "Liang Xingguo said.
The original method of forming Z-DNA is to utilize the plasmid DNA of several thousand alkali-based pairs, which is difficult to freely change the sequence, and it is difficult to identify where to form Z-DNA. "There is only our way to do it, and it is easy."
To form a Z-DNA on the one hand, it can provide raw materials for research. At present, the team of Liang Xingguo has established cooperation with three international research teams, and the drug can also be developed for the treatment of Z-DNA formation related diseases.
He also revealed that the next plan is to continue basic research, accumulating a new understanding of Z-DNA while preparing a stable Z-DNA of various sequences, and cooperating to develop relevant drugs.
"R & D cyclic RNA products have a bright future"
"The earliest (starting in 2006) is to let DNA cycloal, due to difficult to solve the problem of multi-by-products, until 2017, due to the problem of multi-by-products, until 2017 is a preliminary success in the excellent work of Dr. Enron. Later developed to RNA Ringhua, two complementary single-stranded ring hybrids can form lr-chimera or called ZB-Chimera, and the preparation of LR-Chimera containing RNA will be prepared in the future. "
It can be said that the basis for preparing a stable Z-DNA is cycloal, and the cyclization technology is now expected. Liang Xingguo said, "The advantage of cyclization DNA or RNA is that the half-life is longer, and since it is closed, the eutethrase enzyme is avoided, so it is longer in the body. Originally, we have begun to get LR-CHIMERA The ring-stranded nucleic acid cyclization, unintentional development of single-stranded nucleic acid looping techniques, thereby bringing various applications of cyclized single-stranded nucleic acids, especially the cyclic RNA cyclized technologies. "
In 1976, German scientists confirmed that viruses were a single-stranded covalent closed cyclic RNA molecule, which was the existence of cyclic RNA molecules for the first time, but at that time, scientists only saw it as unusual splicing. By-product. With the rapid development of high-throughput RNA sequencing (RNA-SEQ) and cyclic RNA specificity, a large number of cyclic RNAs occur in eukaryotes, and human beings have begun to explore their functions.
Figure of the function and application of annular RNA (Source: BMC)
Compared to linear mRNA, the structure of the annular RNA allows them to avoid nucleic acid external transferase recognition, with higher stability. Based on the above features, cyclic RNA will have a certain advantage in improving the complexity, thermal stability of the production process, increasing RNA therapy, or will provide a new solution for clinical unpacked targets.
However, the main problem of almost all RNA drugs is that there is a short period of time in vivo, and it is still possible for patients whose cancer and rare conditions, but for general diseases, its safety and efficiency have to achieve high levels.
He said, "The body is mainly digestive RNA from the end, but the cyclic RNA will have a certain degree of destruction, and the function of the cyclic RNA drug effect also requires sufficient high concentration, undoubtedly, cyclic RNA due to advantages Obviously, it has a bright research and development prospect. Although there are many difficulties that need to be overcome, mRNA vaccines and related drugs have proven their feasibility. "
He added, "In the industrial conversion, accurate and fast cyclic RNA preparations and scale amounts are still a problem, but this is what the drug research and development company is doing or hopes that someone can do."
Liang Xingguo team is currently actively solving this problem. At present, the team has successfully built an efficient cycle of RNA, which can reach a small amount of production cyclic RNA. He said that if you want to achieve large-scale production, it is urgent to establish Advanced annular RNA production line.
"In September 2021, we have been approved by a" one RNA's cyclization technology "and just signed a technical transfer contract with Guangzhou Jichei. Our technical critical is to redesign the linear RNA sequence, It is more susceptible to cyclization. "He also added:" Although the annular RNA can be prepared by intron self-shear method, the viral component will be introduced, and these viral components will have large immunity to organisms. Original. Our technology has lower immunogenicity compared to foreign-in-chosen, which is not easy to cause the body's immune response. We will be re-designed to link The site can be circulated directly, and there is no need to reduce the difficulty of the subsequent purification process without the need for an additional auxiliary chain, and the mid-by-product is significantly reduced. We hope to provide high-quality raw materials for the development of cyclic RNA, Make our country in this field. "References:
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