The “war on epidemic” is a battle between human beings and viruses, as well as a race between scientific research and time. Since the outbreak of the new coronavirus pneumonia (COVID-19), the majority of scientific researchers have been doing their best to tackle the problem, and the majority of medical workers have been using medication scientifically to save more lives. As of March 4, more than 49,000 people have been cured in China. At the same time, the public is strongly looking forward to the early introduction of effective drugs. In this issue, we invite Ding Sheng, director of Global Health Drug Discovery and Development (GHDDI) and dean of the School of Pharmacy at Tsinghua University, to explain the concepts, methods, and rules of new drug discovery and development. There is a set of rigorous logic and scientific mechanism behind the development of new drugs. The Global Health Drug Discovery and Development Institute (GHDDI), established in Beijing in 2016, is an independently operated, non-profit new drug discovery and development organization jointly sponsored by the Bill & Melinda Gates Foundation, Tsinghua University and the Beijing Municipal Government. By bringing together the world’s top resources and utilizing China’s unique advantages, it builds the world’s leading innovation platform for new drug research, development and translation, and is committed to solving the major disease challenges faced by developing countries, including China, and this year it has also made an important contribution to the research and development of antiviral drugs in China. Nowadays, the public is strongly looking forward to the early introduction of effective drugs. So, how to scientifically develop new antiviral drugs? Drug R&D Strategy for New Coronaviruses There is no shortcut in new drug R&D. It usually takes at least 10 years of R&D cycle and one billion dollars of investment to develop a brand new drug to its final approval for marketing. At the same time, new drug development is a long and thorny road with high risks and high failure rates. Drug discovery and development (including clinical trials) for novel coronaviruses is also a complete and rigorous scientific research system, backed by its own specific scientific rules and strict logic. The new coronavirus pneumonia outbreak is so aggressive that a rapid clinical response and effective therapeutic options are urgently needed. At the same time, the fight against the virus is a long-lasting one, and researchers need to consider both short-term and mid- to long-term approaches to drug development against the new coronavirus. Short-term research focus: In the face of an outbreak, time is of the essence. Adopting the research and development strategy of “new use of old drugs”, i.e., further validating drugs with a certain guarantee of safety that have at least completed clinical phase I, can save preclinical and part of the clinical research time, greatly shorten the time cost of drug research and development, and it is the most effective drug research and development tool for sudden-onset diseases and rapid alleviation of the current epidemic. Medium- and long-term research priorities: the development of innovative therapies that target different populations and have good activity and selectivity against the virus, as well as corresponding protective therapeutic measures, is the key to future prevention and treatment. At the same time, there is a need to minimize the emergence and impact of drug resistance in order to preserve the efficacy of these drugs. What are the potential therapies against novel coronaviruses Potential anticoronaviral therapies can be divided into two categories: those that directly target novel coronaviruses and those that are human-oriented. Since the virus must enter the host cell and replicate in order to function, antiviral drugs can be designed to address a range of targets during virus-cell receptor interactions, gene replication, transcription, and translation as the virus invades the host cell and completes its life cycle. In addition to the above drug development for viruses, therapeutic drugs can also be developed for the human body, targeting the immune response induced by viruses. In the early stage of viral infection, the body’s own immunity can be raised/activated appropriately to fight the virus through the activation of interferon or innate immune receptors. For patients with severe advanced/over-immunized disease, immunosuppressive drugs or mechanisms can be considered for modulation as the patient is subjected to an over-aggressive attack by the autoimmune system. Additionally, therapies can be directed at mechanisms/targets where the host and pathogen are mutually exclusive. Currently, the major therapeutic modalities for the disease include small molecule targeted drugs, biomolecule drugs, gene therapy, cellular therapy, herbal therapy, and medical devices, each of which has the following potential applications in the treatment of neocoronaryngitis. Chemical small-molecule targeted drugs: small-molecule targeted drugs are one of the types of drugs that are currently expected to be used in the treatment of neocoronavirus. Several small-molecule drugs have entered the clinical trial stage, and their effectiveness and safety against neocoronavirus need to be further verified. Class I: Protease Inhibitors Lopinavir/Ritonavir tablets (trade name: Crizal), an antiviral drug developed for HIV, can effectively inhibit the important role of proteases in the process of viral replication and viral function, thereby interfering with the assembly process of the virus to make it non-infectious and ultimately preventing the virus from becoming infected. Low-dose ritonavir can inhibit the hepatic catabolism of lopinavir, achieving the effect of improving the bioavailability of lopinavir. Therefore, the combination of two protease inhibitors can be effective in improving the efficacy of antiviral therapy. There are similarities between the protease activities of HIV and neocoronavirus, but there are differences in the target structures. Therefore, whether this drug is really effective against New Coronavirus needs to be verified by rigorous clinical trials and must be used with caution. Category 2: RNA-dependent RNA polymerase (RdRP) inhibitors Remdesivir (GS-5734) is a nucleoside analog developed by Gilead as a broad-spectrum antiviral drug. The drug was used in clinical trials against Ebola virus infection, but the results were not favorable. Ridecivir acts on RdRP and achieves its antiviral effect by inhibiting viral RNA replication. Previous studies have confirmed the effectiveness of raltegravir against SARS and MERS, and based on the similarity between the catalytic site structure of Neocoronavirus and that of SARS and MERS, it can be hypothesized that this drug may also be effective against the target of Neocoronavirus. The clinical phase III trial for raltegravir has been initiated and is expected to be completed by the end of April this year. Another RdRP inhibitor, Favipiravir (formerly known as “Favipiravir”, Favipiravir), is a class of marketed broad-spectrum antiviral drugs with good therapeutic effects on patients with severe influenza and drug resistance, which is also effective in preventing viral replication in the host cells, and is currently undergoing clinical studies against the new coronavirus. Clinical studies are currently underway for the new coronavirus. In addition to the above two types of drugs, there is also a class of small molecule drugs that can regulate the interaction between the new coronavirus and the host by targeting the host and effectively inhibit the virus from attacking human cells, which may also have certain therapeutic potential. These include the antimalarial drug chloroquine, which has been in clinical use for more than 70 years, hydroxychloroquine, which is used in the treatment of autoimmune diseases, and abidol, which was developed for the influenza virus. These drugs target viral invasion of human cells, cell fusion between the action of the target, and a certain degree of safety is also guaranteed. These drugs have been incorporated into the sixth edition of the diagnostic and treatment program based on the urgent needs of current clinical treatment. Biomacromolecule drugs: the specificity of such drugs is relatively high, the persistence of the drug in the body, compliance is strong, but its production cost is high, and because it only acts on the cell membrane and outside the membrane, can not enter the cell, so there are limitations in the target point. No relevant specific antibodies have been found and clinically tested in the study of new coronaviruses. Meanwhile, by extracting neutralizing antibodies from the plasma of some of those who have recovered from neocoronavirus pneumonia with sufficient concentrations of effective antibodies, the potentially harmful components can be removed and used to treat critically ill patients, but it is unlikely that it will be available on a large scale. Gene therapy, a treatment for disease developed in recent years, usually involves transgenic modifications to compensate for missing functions or to enhance gene function, and a variety of modalities, such as precision gene editing, have been developed. However, there is currently no gene therapy for the new coronavirus, which is generally used for chronic, long-term viral infections, such as gene editing of human cells so that the pathogen loses its ability to infect cells, or inhibiting viral gene expression through RNA interference. Cell therapy is also a means of disease treatment developed in recent years, one of which is to supplement and replace missing cells, such as the use of stem cells; another is to regulate the body’s immunity through cytokines secreted by transplanted cells, which are not supplemented or replaced by the cells, and subsequently such transplanted cells disappear; and there are also transplanted cells that can be targeted to attack specific harmful cells, such as the specific recognition and removal of cancer cells by CAR-T cells. Cell therapy is investigated in the treatment of neococcal pneumonia, such as immunomodulation with mesenchymal stem cells. Tissue repair and regeneration with specific stem cells could be considered in the future; stem cell-derived organoids could be used for disease modeling and drug screening. Protective “therapeutic” approaches: In the long term, researchers need to think not only about how to cure patients with drugs after infection, but also about how to prevent people from being infected by the virus. Protective therapies are drug interventions for healthy people, but they require a high degree of safety. Vaccines, for example, are a common type of protective therapy. It also includes protection by antiviral drugs and protection by immunomodulation. As technology continues to advance, vaccines are being developed at a faster rate, but the risks of research remain high. Even after animal experiments have been completed, there have been cases where, instead of protecting the population, the infection has been exacerbated. Therefore, rigorous clinical safety and efficacy evaluations are still needed. After the safety and efficacy of antiviral drugs have been determined, it makes sense to selectively conduct protective clinical trials of these drugs. In addition, there is also the possibility of facing problems such as insufficient funding after the end of the epidemic and the cost of large-scale production technology, which is months or even years away from actually being ready to be put on the market. Medical device therapy: In addition to drug therapy, respiratory support therapy relying on medical devices, such as oxygen therapy, invasive mechanical ventilation, extracorporeal membrane pulmonary oxygenation (ECMO), circulatory support and other therapeutic modalities, also played an important role in the treatment of severe and critically ill patients with this new coronavirus pneumonia. Traditional Chinese Medicine (TCM) treatment: The new coronavirus pneumonia belongs to the category of “epidemic” disease in TCM, and its research idea is different from that of Western medicines, as it is not aimed at a definite target, but rather cures the disease through a systematic approach. Through in-depth observation and treatment of patients, on the basis of summarizing and analyzing Chinese medicine diagnosis and treatment plans from all over the country, sorting out and screening the treatment experiences and effective prescriptions from all over the country, we need to judge their effectiveness and safety through rigorous clinical trials. How to guide the clinical use of drugs to save lives At present, there is no officially recognized effective drug against the new coronavirus, most potential treatment options are still in the clinical trial stage, and their effectiveness has to be further observed and verified. So what else can people do in terms of clinical use of drugs before a specific drug is available? For drug development, clinical trials are a necessary process. Without adequate verification of a drug’s indications, safety and efficacy, large-scale use of the drug is very risky. However, clinical trials also face many challenges. Randomized controlled trial (RCT), which is characterized by “randomized, controlled, double-blind”, is the “gold standard” of modern medicine to verify the efficacy of drugs. However, RCTs also face many challenges, such as time, rigor of clinical design, irrational selection of controls and randomized groups, insufficient sample size, inadequate control of variables, uncertainty of clinical outcome indicators, and ethical issues, which undermines the quality of clinical research evidence, wastes case resources, and even affects the treatment of patients. In this case, the use of real world evidence, through retrospective cohort studies and case-control studies, to observe more patient performance, preliminary judgment, data integration, can be complementary to RCTs, the preliminary judgment of whether a drug may be effective, and to help the developers of clinical trials to improve and optimize the trial design, to enhance the clinical trial. The results of clinical trials in the real world can be extrapolated. At the same time, clinical trials must strictly follow established research strategies and be conducted in a standardized, scientific and orderly manner. However, in the case of a pressing epidemic, where no specific drug has been verified through clinical trials, solutions such as “off-label use (meaning that a drug that is already on the market is used outside of its approved indications)” and “sympathetic use (meaning that a drug that is not yet on the market is used for treatment within a certain range of circumstances)” can be used. treatment)” and “compassionate use (refers to unlisted drugs that are used in a certain range of special circumstances for treatment)” solutions, where drugs are administered on a small scale for treatment, and then scaled-up applications are discussed after more clinical evidence is available on the efficacy and safety of a particular class of drugs for the treatment of neocoronaviruses. Drug development is a complete and rigorous scientific research system, supported by its own specific scientific laws and strict logic. In the short term, drug development for new coronaviruses can focus on the strategy of “new use of old drugs”, together with highly efficient, rational and optimally designed clinical trials, supplemented by rigorous consideration of other medications, in order to accelerate the treatment of patients. In addition, the cost to the national economy of a new outbreak is far greater than the cost of developing many drugs. Therefore, early preparatory research and development for such public health and major infectious diseases is extremely important and depends on medium- and long-term strategic layout, comprehensive planning, rational allocation of resources and sustainable research investment at the national level. In the face of the raging neocoronavirus epidemic, GHDDI and the School of Pharmacy of Tsinghua University formally opened up their technology platforms, drug discovery and development resources, as well as other new drug discovery and development capabilities to research institutions and researchers from all over the world, aiming at accelerating drug discovery and development of novel coronaviruses with all walks of life.At the end of January, “Targeting 2019 – NCoV”, a one-stop platform of data and information sharing for novel coronaviruses, has been launched. “Targeting 2019-nCoV” has been officially launched, covering real-time tracking of the global research progress of new coronaviruses, analysis of new coronavirus targets, 3D modeling data, as well as the download of historical coronavirus drug discovery data and review of drug discovery strategies, etc., so that drug discovery and development researchers, clinicians and members of the public can track and review the progress of new coronaviruses in real time. and the public can track and query the relevant information in real time. It is expected that with these efforts, we will be able to find effective therapeutic drugs as soon as possible and overcome the difficulties together. Source: Guangming Daily