Sniper covid-19: where are the silver bullets?

With the development of the new crown epidemic, it has already opened a global modelUnfortunately, although covid-19's gene map, protein structure, invasion receptor and other biological related mechanisms have been rapidly explored, so far, in addition to a number of public health measures and medical means, we have limited weapons to fight against virus in medicineThere is no particularly exciting news from radcivir to chloroquineIn the face of the ferocious covid-19, where are our silver bullets? < br / > antiviral drugs: embarrassment in non hot areas < br / > this may start from the research and development situation of antiviral drugsLooking at the territory of new drug research and development, compared with tumor, central nervous system disease, chronic disease and many other hot areas, the popularity of antiviral drugs is not highThe main reasons are the limited ability of patients to pay (typically, HIV is often referred to as the disease of the poor), the uneven geographical distribution (different disease spectrum of people on different continents), the unstable level of disease (epidemic and non annual), the lack of basic research progress in virology, and the partial solution of the problem by the vaccine and public health means< br / > in Europe and the United States, after the successful cure of HCV a few years ago, in addition to a few biotechnology companies and public organizations are still trying to conquer HIV, the overall research and development of antiviral drugs has been decliningThe situation in China is also hard to be optimisticAccording to the statistics of nextpharma database, more than 90% of the anti-virus innovative drugs under research are for HBV, and other virus types are also ignoredIn this context, in the face of the outbreak of cov-2019, it is not surprising that the industry is in a rush< br / > in fact, coronavirus is not new to the academic community, but it has not attracted a lot of public attention for decades, until the outbreak of SARS in 2003 and Mars in 2012This may be due to the previous major pathogenic strains, including hcov-229e, hcov-oc43, HCoV-NL63 and hcov-hku1Most of the infection symptoms are mild and self-healingEven global public events such as SARS and Mars, which spread and died in large numbers, tend to lose their attention as the epidemic subsides< br / > there are still several laboratories devoted to the research of coronavirus in the field of basic scientific research, while in the industry, there is a lack of research in front of the door all the year roundThat's why when covid-19 suddenly broke out, most of the antiviral drugs in the research on SARS and Mars were in pre clinical or at most phase I, and few hands could come outVery helpless, but this is the reality < br / > take history as a mirror: look for weapons against covid-19 < br / > the antiviral drugs of modern concept should be traced back to Idoxuridine approved in 1963 During the next 50-60 years, in the academic and industrial circles, we worked together to fight HIV, HCV, HBV, influenza and other types of viruses Nearly 100 kinds of antiviral drugs were successively developed and listed, including the victory of such milestone level as sophibuvir Whether it is experience or strategy, it should be said that there has been considerable accumulation How can we learn from COVID-19? < br / > check the R & D strategy of antiviral drugs Generally speaking, the life cycle of most viruses mainly includes binding with cell surface receptors, endocytosis, releasing genetic material, transcription or reverse transcription (some may also be integrated into the host genome), protein translation and cutting, as well as the assembly, maturation and release of viruses, and also involves the utilization of some host organelles With the different kinds of virus, the specific path may be slightly different, but there are basically traces to follow So far, the development strategy of antiviral drugs is also trying to solve these problems < br / > according to the classification, coronavirus belongs to linear positive strand single strand RNA virus Similar to SARS CoV and Mars CoV, covid-19 genome encodes and expresses four kinds of non structural proteins: plpro and 3clpro, helicase, RNA polymerase and spike glycoprotein Four kinds of nonstructural proteins are the key enzymes in the life cycle of covid-19, and structural protein S is the key role in the process of virus binding and entering cell surface receptor < br / > genome map of cov-2019 < br / > human and RNA viruses have been involved for many years, including HIV, Ebola, influenza, HCV and so on This may provide us with some experience in fighting against covid-19 Let's look at it in turn < br / > the first step of viral entry inhibitors < br / > is to change the conformation and start the following steps by binding the ligand protein to the specific receptor on the cell surface The strategy of inhibiting virus invasion is to block the binding between virus and receptor, including the receptor targeting virus or host cell Currently, FDA has approved a number of invasion inhibitors, including small molecules (maraviroc, targeting HIV CCR5), peptides (hiv-gp41 homologous sequence) and macromolecules (palivizumab, targeting RSV glycoprotein f) < br / > although experience shows that the strategy of blocking the invasion is not effective in all viruses, fortunately, there may be opportunities for coronaviruses No matter from the previous animal model study of Mars cov or the treatment of the serum of convalescent patients found out in the covid-19 epidemic situation, all showed positive signals The structure of S protein has been successfully resolved and published in Science in February < br / > s protein structure of covid-19 < br / > according to the public news reports, including vir biotechnology, abcellera, regeneron and other companies are screening monoclonal antibodies against S protein In addition, Wuxi apptec has also reached a joint development intention with immunoprecise < br / > in addition to the virus surface matching, the development of drugs for the surface receptors of virus host cells is also a strategy to block virus invasion The receptor of covid-19 is ACE2, which is similar to SARS CoV The main idea of targeting ACE2 is to select the suitable sequence of S protein to synthesize peptide There are also many attempts in this area, and we can combine the previous research experience of SARS CoV < br / > nucleoside analogues < br / > nucleoside analogues are probably the most mentioned strategies in the current anti-virus drug development attempts for covid-19, mainly because this kind of drugs have had successful cases against various types of viruses, and also obtained successful drugs including entecavir In addition, compared with other strategies, the characteristics of nucleoside analogues targeting viral nucleic acids determine that they have more broad-spectrum potential Many drugs under research or on the market can be directly used to try Of course, as a drug developed for the RNA virus covid-19, the scope of selection is mainly within the nucleoside analogues that can be used as RNA polymerase inhibitors < br / > among the drugs on the market, ribavirin, approved by Roche, is a guanine analogue, which can effectively inhibit the RNA polymerase activity of a variety of RNA viruses Previously, it has been approved for the indications of HCV, RSV and HSV Moreover, it has also been tried in the groups of patients infected with SARS CoV and Mars CoV, which is a promising candidate drug In addition, fabiravir, which has pulled several limit plates for Haizheng, is also a listed broad-spectrum antiviral nucleoside analogue with similar mechanism < br / > in the research of drugs, the nature with the highest heat is called "people's hope" (remdesivir) Radcivir has been mainly developed for Ebola before, and has shown certain activity in cell and animal experiments of SARS CoV and Mars cov Its clinical trial used in covid-19 has long been the focus of attention I wonder if we can get positive results at last < br / > another adenine derivative under development, galidesivir (bcx4430), may also have an opportunity Galidesivir was originally developed for HCV, and has accumulated a number of clinical data for healthy people It has also seen a certain degree of efficacy in patients infected with yellow fever virus It is said that there are some positive data in preclinical experiments for a variety of RNA viruses, including SARS CoV and Mars cov < br / > although nucleoside analogues have the potential of broad-spectrum antiviral, the biggest challenge may be the corresponding low specificity According to the disclosed data of in vitro cytological study for covid-19, the EC50 of ribavirin is 61.88 μ m, and that of rhetcivir is 0.77 μ m, which is not particularly brilliant, which also makes it possible to achieve the target antiviral effect in clinical use with a higher dose, but at the same time, it may bring security risks < br / > protease inhibitors < br / > protease is the key cutting and assembly element of the genome expression of various types of viruses, and therefore is an important target for the development of antiviral drugs At present, the most successful type of antiviral drugs targeting protease development should be HIV and HCV Several protease inhibitors have been approved, especially the NS3 / 4A protease inhibitor of HCV has become a classic milestone < br / > like SARS CoV and mar CoV, covid-19 also expressed two proteases: 3clpro (3-chymotrypsin like protease) and plpro (papain like protease) Previously, it has been reported that many compounds can inhibit the 3clpro or CLPRO activities of different kinds of coronaviruses in vitro, but they fail to inhibit the replication of the virus, and the broad-spectrum is not very good < br / > among the approved protease inhibitors, lopinavir and ritonavir from abbvie and dispfiram from Teva have been reported to have antiviral activities against SARS CoV and Mars cov Lopinavir and ritonavir are speculated to target 3plpro Previously, some positive results have been reported in primate models and SARS CoV infected patients However, as inhibitors for HIV protease development, the final efficacy of covid-19 remains to be observed Disulfiram targets aldehyde dehydrogenase, which is used to treat alcohol addiction Although the indication is not antiviral before, some studies have shown that it can inhibit plpro of coronavirus, but there is no clinical evidence < br / > in addition, it has been reported recently that vinylsulfone, as a protease inhibitor, shows nm level activity in inhibiting covid-19 replication, but its exact mechanism may need to be further explored < br / > host targeted agents < br / > in addition to the key elements of the targeted virus, targeting host regulation is also one of the strategies to develop antiviral drugs, the first one to be hit is to activate the host immune system Many viruses, including coronaviruses, have the ability to suppress the host immune system, thus avoiding the immune response Therefore, reactivating the host immune response is also considered to improve the antiviral effect of the body < br / > recently, the most active antiviral immunomodulator is chloroquine, which has carried out the so-called 10000 person clinical trials in the UK In addition, nitazoxanide, which is used for the treatment of diarrhea, is also promising The antiviral activities of these two compounds in vitro were 1.13 μ m and 2.12 μ m, respectively In addition, various types of interferon are believed to contribute to the treatment of covid-19 < br / > however, objectively speaking, most of the successful antiviral drugs in the past are targeted at viruses In contrast, the antiviral drugs developed for the host still have great limitations in accuracy, safety and other aspects, and the real successful cases are very limited For example, in the treatment of HBV, the use of interferon drugs has become less and less Conclusion: as a whole, at least up to now, there are not many antiviral drugs that may be effective in the face of covid-19 In the final analysis, it is because of the limited attention of academia and industry to coronavirus It makes me