A novel coronavirus as an example to analyze the future direction of new drugs for severe pneumonia

Original by Li Jiamin The novel coronavirus pneumonia since December 2019 has affected the hearts of millions of people Severe cases in infectious patients, like severe cases of SARS, highly pathogenic avian influenza and influenza A / B virus pneumonia, all point to the same term severe pneumonia What is the sacred side of severe pneumonia? What is the difference between severe pneumonia and general pneumonia? How to find out the long-term potential investment target? We can see the following explanation Pneumonia is mainly caused by bacterial or viral infection, less from fungi and parasites Bacteria are the most common cause of community-acquired pneumonia Streptococcus pneumoniae is isolated from nearly 50% of cases Other bacteria include 20% Haemophilus influenzae, 13% Chlamydia pneumoniae and 3% Mycoplasma pneumoniae Viral pneumonia accounts for 1 / 3 of adult pneumonia cases and 15% of children's pneumonia cases The common pathogens involved include rhinovirus, coronavirus, influenza virus, respiratory syncytial virus, adenovirus and parainfluenza Although the pathogenesis of novel coronavirus is complex, here, Xiaobian takes the pathogenesis of new coronavirus as the starting point to elaborate the pathogenesis of severe pneumonia Coronavirus is a enveloped, segmentless, just single stranded RNA virus genome, with a size range of 26 to 32K bases, which is the largest known RNA genome virus The virus has a nucleocapsid composed of genomic RNA and phosphorylated Nucleocapsid (n) protein, which is embedded in phospholipid bilayers and covered by two different types of spike proteins: spike glycoprotein trimer (s), which can be found in all CoVs, and hemagglutinin esterase (he) in some CoVs Membrane (m) protein (type III transmembrane glycoprotein) and envelope (E) protein are located between the S protein of virus envelope Figure 1 coronavirus structure, from reference [1] The subfamily of coronaviruses is divided into four genera in genotype and serology, i.e α, β, γ and δ coronaviruses β - coronavirus can be further divided into four virus lineages, namely A-D lineage There are nearly 30 recognized cov infections in humans, mammals, poultry and other animals Human coronavirus infection is caused by α - and β - CoV During the period of coronavirus infection, host factors will trigger the immune response to the virus, including innate immune response and adaptive immune response Important immune pathways involve: CoV infects macrophages, which then present cov antigens to T cells This process leads to the activation and differentiation of T cells, including the production of cytokines related to different T cell subsets (i.e Th17), followed by the release of a large number of cytokines for immune response amplification Because of the persistence of the virus, the continuous production of these mediators has a negative effect on the activation of NK and CD8 T cells However, CD8 T cells will produce very effective mediators to remove cov CoV is attached to dpp4r of host cell through S protein, which leads to the appearance of genomic RNA in cytoplasm In the process of cov replication, part of the immune response to dsRNA can be produced DsRNA sensitized TLR-3 and a series of signaling pathways (IRF and NF - κ B activation, respectively) were activated to produce type I IFN and proinflammatory cytokines The production of type I IFN is essential to enhance the release of antiviral proteins and protect uninfected cells Sometimes, the cofactors of coronavirus can interfere with TLR-3 signal transduction and bind to dsRNA of coronavirus in the process of replication, so as to prevent TLR-3 from activating and avoiding immune response TLR-4 may recognize s protein and activate proinflammatory cytokines through MyD88 dependent signaling pathway The interaction between virus and cell leads to a large number of immune mediators In response to cov infection, infected cells can promote the secretion of a large number of chemokines and cytokines (IL-1, IL-6, IL-8, IL-21, TNF - β and MCP-1) These chemokines and cytokines then recruit lymphocytes and leukocytes to the site of infection Figure 2 human immune response induced by coronavirus, from reference [1] It seems that chemokines play an important role in immune response to virus infection because of their role in regulating the expansion and location of leukocytes in host Therefore, the change of chemokines may lead to serious immune response disorder Immune dysfunction increases virus replication and leads to tissue damage On the contrary, overactive immune response may induce immunopathology, which will result in lung tissue damage, function damage and lung capacity reduction When the inflammation of lung tissue (bronchioles, alveoli, interstitium) develops to a certain stage of disease, the deterioration aggravates the formation, causes organ dysfunction and even endangers life, and severe pneumonia erupts The treatment of severe pneumonia includes drug treatment, respiratory support, systemic organ function support and protection At this stage, the development of new drugs for severe pneumonia complications aside, this time we will first look at the new drugs that are expected to treat severe pneumonia 17 new drugs under research are summarized in the small edition, of which the number of small molecule drugs and biological agents is equivalent (9:8) See the table below for details It is not hard to see that the development of small molecule drugs is mainly based on antibiotics In the current environment of domestic anti drug restrictions and the declining capital market of overseas antibiotic enterprises, small editors are pessimistic about the market after the listing of such drugs The traditional treatment of pneumonia is mainly antibacterial, supplemented by immunoglobulin The emergence of antibody drugs has opened up a new track for the pneumonia market, which also means a big change in the treatment mode With the development of 2019-ncov epidemic, including vaccines, small molecule drugs, recovery patients' serum, neutralizing antibodies and other drugs have become the mainstream means to fight the epidemic Nature review recently provided a list of 65 potential compounds for 2019-ncov For details, please refer to "theoretical options for the 2019 new corona virus (2019-ncov)" But the drugs on this list are mainly antiviral drugs for viruses However, there are not many new drugs for acute lung injury and respiratory distress symptoms induced by virus infection Compared with the limitations of the future indications of direct antiviral drugs, the symptomatic drugs for severe pneumonia will obviously have greater use space in the future After all, it's not the end of an epidemic, it's a broad-spectrum drug that's ready to respond to the resurgence of another new virus (hopefully not) In the current research of drugs, we also found that the active drugs for severe pneumonia are mainly bacterial toxins and immunosuppressant pathway All in all, the development of new pneumonia drugs, rather than blindly following the trend and touting the capital market, is better to have a deep understanding of the host's defense against the lung tissue inflammation induced by pathogenic pathogens, such as coronavirus, and the role of innate immune system in pathogenesis and clinical treatment It is more sustainable and broad space to develop drugs according to symptoms.