The global prevalence of new coronavirus has made mRNA vaccine a great success in the market, promoted the development and maturity of nucleic acid drug research and development and technology platform, initially demonstrated its potential and energy to the global pharmaceutical industry, and become a major pillar of the third revolution in biotechnology.
△ Up to now, the list of nucleic acid drugs approved worldwide (data source: Kerui Weian)
The three revolutions of biotechnology embodied the multi-level regulation of life science, and the different links of the targeting center rule gave birth to the differentiation strategy of drug research and development. The past technological innovation has made remarkable progress in drug targeting and diversity of targets. The biggest advantage of nucleic acid drugs is that they can be designed quickly and intuitively based on base sequence, using simple preparation materials and processes, affordable production costs, greatly shortening the drug development cycle, and making it possible to customize or personalize treatment plans, This has solved the knotty problems besetting the current pharmaceutical industry, such as rare diseases. Such drug design strategies are also known as programmable medicine.
△ Around the central principle, the research and development strategy of nucleic acid drugs has been differentiated. 【1】
The straightforward programming thinking of programmed pharmaceutical preparation provides an axe to solve the complicated and mysterious life science, and the discovery and application of CRISPR/Cas9 system make it possible. Crisper/Cas9 system is an efficient and controllable DNA splicing tool. Cas9 protein is activated by guiding RNA molecules to play the role of recognizing and cutting genomic DNA. Ribozymes are RNA with catalytic activity, which can degrade specific mRNA sequences. The use of nucleic acids with specific sequences as drugs breaks the traditional way that drug therapy can only act on target proteins. The candidate targets of these nucleic acid drugs are rich and the indications are widely distributed.
△ Crispr/Cas9 can be like a pair of scissors to knock out specific gene sequences, so as to achieve the effect of gene editing.
However, the human body is not a simple binary program after all. On the way to put programmed drugs into practice, researchers found that there are many obstacles to overcome. Because of the complex structure of the human body, there are many different mechanisms involved in each other to jointly maintain the harmony and stability of the body and resist the invasion of foreign substances.
The human body is not friendly to nucleic acids. First of all, nucleic acid molecules have short half-life and are easy to be absorbed and cleared by the kidney, which leads to poor stability in the human body; Second, a variety of nucleases in the blood can easily degrade nucleic acids; Third, nucleic acid substances can activate some immune recognition receptors, such as TLR3/7/8, causing immunogenic reactions; Fourth, because nucleic acid usually has a large molecular weight and carries negative charges, it is difficult for it to be absorbed by cells through the membrane structure, so that the drug can successfully reach the target position to play its role; Fifthly, there are relatively few nucleic acid drugs with relatively complete pharmacokinetic (ADME) data, and the particularity of their structures requires innovation and change in the development of pharmacokinetic methods; Finally, the potential side effects that are similar to genes and genetic materials are worrying
In order to enable nucleic acid drugs and programmed medicine, the research and development of nucleic acid drugs has also spawned many new technologies. Medici has also stepped up its layout in this revolution, and has formed a complete nucleic acid drug research and development platform to meet the challenges and difficulties that may be brought by nucleic acid drug research and development.
Chemical Modification Technology of Nucleic Acid
The chemical modification of nucleic acid mainly includes the modification of base, sugar ring and connecting group phosphoric acid, so as to overcome the disadvantages of unstable nucleic acid drugs in the blood and short half-life, and strengthen some advantages and functions. For example,
The incorporation of 2 'chemical modification (2' - F, 2 '- OMe, 2' - MOE, etc.) greatly improved the stability and overall half-life of nucleic acid;
Enhance target affinity
Improve bioavailability
Thiophosphorylation reduces renal clearance
In the discovery and research stage of nucleic acid drugs, we can help customers complete the synthesis and chemical modification of various monomers and oligomers, and complete the high throughput screening of targets and early pharmacokinetics to obtain nucleic acid compounds with good targeting and stability.
Monomer synthesis
Oligonucleotide Synthesis 
Sugar modification
base modification 
Skeleton decoration
Synthesis of oligonucleotide conjugates
siRNA
ASO/gapmer