Empowering nucleic acid drug therapy to meet the third wave of new drug research and development

    The three revolutions in biotechnology reflect the multi-level regulation of life sciences, and the different links of targeting the central dogma have promoted differentiated strategies for drug development. The previous technological innovations have made remarkable progress in the targeting of drugs and the diversity of targets. The biggest advantage of nucleic acid drugs different from previous technologies is that they can be designed quickly and intuitively based on the base sequence, using simple preparation. Raw materials, processes, and affordable production costs have greatly shortened the cycle of drug research and development, which made it possible to customize drugs or personalized treatment plans, and solved the thorny problems currently plaguing the pharmaceutical industry such as rare diseases. Such a drug design strategy is also aptly called Programmable Medicine.

The discovery and application of the CRISPR/Cas9 system made it possible for Programmable medicine to provide an axe to the complex and mysterious life sciences with straightforward programming thinking. The Crisper/Cas9 system is an efficient and controllable DNA shearing tool. The Cas9 protein is activated by guide RNA molecules to recognize and cut genomic DNA. Ribozymes are catalytically active RNAs that degrade specific mRNA sequences. The use of nucleic acids with specific sequences as drugs breaks the way that traditional drug treatments can only act on target proteins. The candidate targets of these nucleic acid drugs are abundant and the indications are widely distributed.

However, the human body is not a simple binary program after all. On the way to putting programmed drugs into practice, researchers have 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 maintain the harmony and stability of the body and resist the invasion of foreign substances.

    The human body is very unfriendly to nucleic acids. First, nucleic acid molecules have a short half-life and are easily absorbed and cleared by the kidneys, which has 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, resulting in an immunogenic reaction. Fourth, because nucleic acids usually have a large molecular weight and carry a negative charge, it is difficult to be absorbed by cells through the membrane structure, allowing the drug to reach the target site smoothly to exert its efficacy. Fifthly, there are relatively few nucleic acid drugs with relatively complete pharmacokinetic (ADME) data, and the particularity of their structure requires innovation and change in pharmacokinetic method development. Finally, worrisome potential side effects similar to genes and genetic material...

In order to empower nucleic acid drugs and programmed pharmaceuticals, the research and development of nucleic acid drugs has also spawned many new technologies. Medicilon has also stepped up its layout in this revolution, and has now formed a complete nucleic acid drug research and development platform to meet the challenges and difficulties that may be brought about by nucleic acid drug research and development.

The chemical modification of nucleic acid mainly includes the modification of base, sugar ring and linking group phosphate, so as to overcome the disadvantages of nucleic acid drugs such as instability in blood and short half-life, and strengthen certain advantages and functions. For example:

In the discovery and research stage of nucleic acid drugs, we can help customers to complete the synthesis and chemical modification of various monomers and oligomers, and complete various high-throughput screening of targets and early pharmacokinetics to obtain good targeting , nucleic acid compounds with good stability.
Monomer synthesis

    The innovation of the drug delivery system is a significant step for the development of nucleic acid drugs. It enables the nucleic acid molecules that are originally fragile in the human body to be safely delivered to the target position, and can smoothly bind to the target to play a role. This is due to the increasing maturity of lipid nanoparticles (LNP) and GalNac coupling technology, which are usually composed of cationic lipids, cholesterol, PEGylated lipids and phospholipids, which help to mask the charge carried by nucleic acids and protect itnot to be degraded by nucleases. Chemical modifications can also help improve the delivery efficiency of nucleic acid delivery.

    Although nucleic acid drugs have undergone some chemical modifications, and most of the small nucleic acid drugs are mostly by chemical synthesis, their basic structure and physical and chemical properties still have many similarities with the nucleic acid substances in the body, so they will produce biological effects in the body to varying degrees. It has a far-reaching impact on a series of manifestations such as pharmacology, metabolism and toxicity of drugs in vivo. In the preclinical research of nucleic acid drugs, biological analysis is an indispensable process.

    On the one hand, the problem to be solved by bioanalysis is how to quantify in vivo after drug administration. Since the purpose of therapeutic oligonucleotides is to alter biological targets, it is necessary to accurately determine their concentrations in biological samples, as well as to identify metabolites produced in vivo that are potentially active and may cause off-target toxicity. The tissue distribution of nucleic acid drugs is also important. Many therapeutic oligonucleotides either have a targeting moiety built into their structure or will use a delivery system to facilitate the drug's entry to the target to increase its concentration in specific organs. Modifications of these biopharmaceuticals (such as phosphorothioation, conjugation with N-acetylgalactosamine (GalNac), etc.) not only improve in vivo stability, targeting specificity, and overall titer, etc., but also bring more challenges and opportunities to the analysis of phosphoric acid drugs.On the other hand, nucleic acid drugs have potential immunogenicity, so the analysis of the possible immunological effects of nucleic acid compounds and the body is also a research work that must be completed.

    Progress and breakthroughs in nucleic acid drug research have brought the dawn of treatment for more diseases, especially chronic diseases such as genetic metabolic diseases. When we evaluate the druggability, safety and effectiveness of nucleic acid compounds in the preclinical stage, we need to pay attention to the many issues mentioned above, and use multiple technology platforms, such as animal pharmacodynamic model, mass spectrometry analysis, and immunogenicity analysis. , cell biology and molecular biology, etc., to provide in-depth and comprehensive drug data, and lay a solid foundation for the research process of nucleic acid drugs.

    Raference：
【1】Mollocana-Lara EC, Ni M, Agathos SN, Gonzales-Zubiate FA. The infinite possibilities of RNA therapeutics. J Ind Microbiol Biotechnol. 2021;48(9-10):kuab063.
【2】Aldosari et al., (2021). Lipid Nanoparticles as Delivery Systems for RNA-Based Vaccines. Pharmaceutics, https://doi.org/10.3390/pharmaceutics13020206.