The novel coronavirus epidemic is still spreading globally. In addition to vaccines, people also hope for specific drugs. At present, more and more drug candidates have entered the field of vision of scientific researchers, and a large number of clinical trials are being carried out globally, but the real novel coronavirus specific drugs have not yet appeared.
So, what is the progress of the research and development of novel coronavirus specific drugs? Where is the breakthrough? How long will it take for real special effects to be available?
Search for potential targets
To develop specific antiviral drugs, we must first screen and design drug targets based on the key mechanisms of the new corona virus invading human cells, self-replication and pathogenicity.
Li Wenhui, a researcher at the Beijing Institute of Life Sciences, recently told reporters that the known new corona drug targets can be divided into two categories, one is to target the new coronavirus itself; the other is to target the human body. Targets that target viruses can also be subdivided. One type is for the virus invasion stage, such as spike proteins that help the virus invade cells, and its receptor binding domain (RBD) is a key target; the other is for the virus replication stage. Among them, the main protease and "RNA-dependent RNA polymerase (RdRp)" are considered to be two more promising targets.
The main protease is like a "magic scissor". There are at least 11 cleavage sites on the new coronavirus replicase polypeptide. Only when these sites are correctly cleaved can these viral replication-related "parts" be successfully assembled into replication transcriptions. The machine starts virus replication. RdRp is like the core "engine" of viral RNA (ribonucleic acid) synthesis. With it as the core, the virus will cleverly use other auxiliary factors to assemble an efficient RNA synthesis machine to replicate itself.
Researchers have so far successfully observed the structure of multiple new coronavirus targets. Related research has laid a solid foundation for the research and development of novel coronavirus drugs.
The US scientific research team first reported the three-dimensional structure of spike protein on the atomic scale in February. In March, the team of Shanghai University of Science and Technology and Tsinghua University analyzed the three-dimensional spatial structure of near-atomic resolution of the "engine" "RdRp-nsp7-nsp8 complex", the core "engine" of the transcription and replication machine. Institutions such as Shanghai University of Science and Technology and the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences reported in April a powerful inhibitor of the main protease, N3, and the first to analyze the structure of the "main protease-N3" high-resolution complex.
Drug targets that target the human body are more complicated, because the symptoms of the new coronavirus infection are diverse, affecting multiple organs. From a therapeutic perspective, more such targets are still being explored, some of which target the immune system.
Go in multiple directions
According to experts, the novel coronavirus drugs under investigation basically cover common types of drugs, and have made progress in small molecule targeted drugs and biological macromolecular drugs. In the future, other candidate therapies such as stem cell therapy and gene therapy may also appear.
In the field of small molecule drug research and development, multiple teams have reported new discoveries of candidate compounds targeting the main protease, and believe that these compounds have the potential to develop into novel coronavirus drugs. After the SARS epidemic, researchers at the University of Lübeck, Germany, developed alpha-ketoamide antiviral compounds targeting the main protease, and published cell test data for its "improved" alpha-ketoamide 13b in May this year. Australian researchers confirmed through computer simulation that it can effectively prevent the replication of the new coronavirus.
The United States "Science" magazine on June 19 introduced two compounds 11a and 11b targeted by the main protease found by the Chinese scientific research team in the form of cover articles. The research team not only analyzed the interaction mode of the two compounds with the new protease of the new coronavirus, but also revealed the molecular mechanism of their inhibition of the main protease.
In the research and development of biomacromolecule drugs, multiple teams around the world have reported monoclonal antibodies against the new coronavirus. The recombinant fully human anti-novel coronavirus virus monoclonal antibody injection jointly developed by the Institute of Microbiology of the Chinese Academy of Sciences and Shanghai Junshi Biomedical Science and Technology Co., Ltd. was recently approved for clinical trials and is expected to be used for the prevention and prevention of novel coronavirus infections in the near future. treatment.
The development of this drug candidate is based on the monoclonal antibody CB6 isolated from Xinguan rehabilitation patients by the Chinese scientific research team. The British "Nature" magazine published a report online in May that in animal experiments using rhesus monkeys, CB6 showed the ability to prevent and treat novel coronavirus infections, which highly overlaps with the spike protein RBD binding site and host cells, and is higher than the host. The cells are more "affinity" and have a clinical prospect.
"Old medicine" shows new effects
"Old drugs and new uses" is also one of the main R&D strategies of novel coronavirus drugs. If you can find drugs that are effective for new coronavirus infection from existing drugs, you can bypass pharmacological research, animal experiments and other stages and directly enter clinical trials.
The common corticosteroid hormone dexamethasone has been shown to reduce the risk of death in patients with dangerous re-crown. The leading team of the University of Oxford in the United Kingdom used dexamethasone in more than 2,000 patients with severe novel coronaviruss in clinical trials. This drug can reduce the risk of death for patients who require a ventilator by 35%, and reduce the risk of death for patients who require oxygen inhalation by 20%. The World Health Organization has called for increased production of the drug.
Drugs such as redisevir, fapiravir, tocilizumab, etc. have also shown some clinical effects in different novel coronavirus patient groups, but the clinical effect of hydroxychloroquine, which was once hoped for, is not as expected.
"What are the effects of some old drugs on (new coronavirus) known targets and known mechanisms, and now there are some new clinical trial results." said Ding Sheng, director of the Global Health Drug R&D Center and dean of the School of Pharmacy, Tsinghua University The progress of relevant trials helps to define the “old drugs” applicable to the patient population, achieve more precise medication and propose new combination medication methods.
Ding Sheng also emphasized that "old drugs" are not drugs developed for new coronaviruses after all, and researchers still have to use the proven targets to develop new special drugs for novel coronaviruss. The basic research field has accumulated a lot for the development of novel coronavirus drugs. However, there is no shortcut to the development of new drugs. The development of a new drug to the final approval may require a period of up to 10 years and hundreds of millions of dollars of capital investment. There are specific scientific laws and strict logic behind the research and development of new coronavirus drugs, which cannot be achieved overnight.
