Why is it so Difficult to Develop a New Drug to Treat a Corona Virus Infection?

Yesterday, the Shanghai Institute of Materia Medica and the Shanghai University of Science and Technology of the Chinese Academy of Sciences announced that a joint emergency research team “uses the experience accumulated in previous anti-SARS drug research to carry out anti-2019-nCov drug research” and has found a number of “possible for new pneumonia. Therapeutic effect “molecule. As soon as the news was announced, swipe the screen in the circle of friends.

WuXi AppTec’s content team pays tribute to these researchers who are still working on the Spring Festival holiday. In this article, we will combine a review published in 2016 by Nature Reviews Drug Discovery, an authoritative journal in the field of drug discovery. Share the strategies and potential bottlenecks available in the development of anti-coronal drugs.

Three strategies to develop new drugs

Prior to the outbreak of this new corona virus, we only knew about two corona viruses that cause serious health problems to humans, namely SARS and MERS. In the fight against these two viruses, scientists have come up with three strategies for developing new drugs.

The first strategy is to test existing broad-spectrum antivirals. Interferons, ribavirin, and cyclophilin inhibitors used to treat corona virus pneumonia fall into this category. The advantages of these therapies are that they have already been approved for marketing and treat different viral infections. Therefore, their metabolic characteristics, dosages used, potential efficacy and side effects are clear. But the disadvantage is that these therapies are too “broad-spectrum” and cannot target corona viruses in a targeted manner. In addition, its side effects should not be underestimated.

The second strategy is to use existing molecular libraries and databases to screen for molecules that may have a therapeutic effect on coronavirus. This strategy can perform high-throughput screening in a short period of time, and can also test many drug molecules that would not have been considered, expanding our horizons. A few days ago, the anti-HIV infection drug lopinavir / ritonavir (lopinavir / ritonavir) has also been discussed. 

However, the review of Nature Reviews Drug Discovery also mentioned that although many drugs exhibit good anti-coronary virus activity in vitro, they often do not have the value of human application in vivo. The reason is, on the one hand, because of the possible side effects of immune suppression, and on the other hand, because the concentration required for the drug to work, it often exceeds the upper limit of the serum drug concentration.

The third strategy is the most direct-based on the genomic information and pathological characteristics of different corona viruses, there is a targeted development of new drugs from scratch. Theoretically, these therapies will have better anti-coronal virus effects, but it needs to verify the metabolism and side effects of different drugs in humans. It also needs to conduct clinical trials in animals and humans in order to see if they are safe and effective. This process can take years, or even more than 10 years. For acute outbreaks, it is clear that “far water cannot save near fire.”

What potential treatments have there been in the past?

Potential anti-coronal virus therapies can be divided into two categories according to the target, one is acting on the human immune system or human cells, and the other is acting on corona virus.

In terms of the human immune system, the innate immune system response plays an important role in controlling the replication and infection of corona virus, and interferon is expected to enhance the immune response. Considering that corona virus often inhibits the effect of interferon, providing recombinant interferon or providing an interferon inducer may be a countermeasure. In addition, interferon in combination with ribavirin or the HIV infection drug lopinavir / ritonavir has also been seen in the treatment of SARS and MERS two corona viruses.

Some potential therapies for the human body (Data source: Reference [1]; Mapping: WuXi AppTec Content Team; Note: This form is for information sharing only, not a recommended treatment. Please refer to Reference [1] for the complete form; 2016 The data after the year is not included)

However, in this review of the Nature Reviews Drug Discovery, the authors also mentioned that the effect of the combination therapy of interferon and ribavirin is not stable. The reason behind this may be that the patient will not be treated until after the onset of symptoms.

In human cells, blocking the signal pathways required for virus replication may play a certain antiviral effect. Cyclosporine (cyclosporine) falls into this category. However, because this drug can inhibit the body’s immunity, the use conditions are relatively limited. Similar drugs without immunosuppressive side effects may have therapeutic potential.

In addition, viruses often bind to receptor proteins on the surface of cells in order to enter human cells. For example, the SARS virus binds to the ACE2 receptor and the MERS binds to the DPP4 receptor. Previously, several drugs have been developed for these receptors, some of which have been evaluated for safety. In terms of suppressing corona viruses, their effects are also worth looking forward to.

Some potential therapies for corona virus (Data source: Reference [1]; Mapping: WuXi AppTec content team; Note: This form is for information sharing only, not a recommended treatment. Please refer to reference [1] for the complete form Data not included since 2016)

The therapies that act on the corona virus itself can be divided into several categories based on the specific pathways: there are some acting on the genetic material of the virus, preventing the synthesis of viral RNA; and some acting on the enzymes that are critical to the virus, further Inhibits virus replication; there are also structural proteins that act on the virus, block the virus from binding to human cell receptors, or inhibit the virus’s self-assembly process. But as mentioned above, the new drug development process for viruses is long, and many have not yet entered human clinical trials.

We also remind readers that these potential therapies are targeted at both SARS and MERS corona viruses, and that the review paper was updated in 2016, which does not mean that they also have the potential to treat this new type of corona virus. Therefore, the various therapies mentioned above are only for information analysis and reference, not specific medical recommendations.

Bottlenecks in new drug development

In this review of the Nature Reviews Drug Discovery, the authors also mentioned the bottlenecks in the development of new drugs for the treatment of corona virus infections. First, we lack the right animal models. You know, many of the new drug molecules that we have screened have no precedent for use in humans, so large-scale safety and effectiveness studies are essential. To do this, we need multiple small animal models, as well as non-human primate models. Although scientists have done a lot of development, many primate models do not reflect all the characteristics of corona virus infection, so they have limited reference value.

The second bottleneck is the limitation of the characteristics of the drug itself. Some drugs do not achieve the required concentration in the body to work, while others cause unacceptable side effects. The diversity and susceptibility to mutation of corona viruses has determined that drugs developed against one corona virus may not be applicable to other corona viruses. In other words, the new drugs that we have spent years developing may still be helpless or have little effect in the face of the new corona virus.

▲ Some therapies for treating SARS (Data source: Reference [1]; Mapping: WuXi AppTec content team; Note: This form is for information sharing only, not a recommended treatment. Please refer to reference [1] for the complete form; Data not included since 2016)

The third bottleneck is the design of clinical trials. From past experience, corona viruses other than SARS and MERS can cause extremely mild symptoms. Even the SARS virus has disappeared more than 10 years ago, and no new cases have been reported. Although the MERS virus still occurs occasionally, the cases are very scattered. All these make the design of clinical trials difficult. Failure to effectively recruit enough patients and variable control will prevent us from testing how well these new drugs work.

Conclusion

In summary, the development of innovative therapies for corona viruses is by no means an overnight effort. This requires the participation of a large number of scientific researchers, clinical research and development personnel, and even patients and medical personnel. We thank all the scientists who are looking for potential therapies, and look forward to these efforts, we can find a good way to effectively treat the new type of corona virus pneumonia at an early date.

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