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On December 5, researchers at the University of Cambridge in the United Kingdom published an article in the journal Nature called "FXR inhibition may protect from.
"
SARS-CoV-2 infection by reducing ACE2"
.
The researchers identified the FXR receptor (FXR, farnesoid X
receptor) in controlling angiotensin-converting enzyme 2 (ACE2) expression and provides evidence that
modulating this pathway helps reduce coronavirus infection.
The article states that "in human lungs, mouse cholangiocytes and intestinal organoids and their corresponding tissues, the over-the-counter compound ZGG (z-guggulsterone) and the generic drug ursodeoxycholic acid (UDCA) were used to reduce FXR signaling and downregulate ACE2"
.
ACE2 levels were found to be reduced
in organoid models of the lungs, intestines, and bile ducts treated with these drugs.
Due to the close relationship between ACE2 and coronavirus infection, it also indirectly indicates that these drugs may play a role
in controlling new coronavirus infection.
Since the outbreak of the new crown epidemic, ACE2 has been repeatedly mentioned
.
It is commonly understood that ACE2 is located on the human cell membrane and is the main channel
for the new coronavirus to enter and infect human cells.
Theoretically, controlling ACE2 can reduce the invasion
of the new coronavirus into the human body.
Therefore, from the perspective of disease prevention and control, ACE2 may become a breakthrough in the decision to prevent and control new crown infection
.
At present, researchers at the University of Cambridge in the United Kingdom have demonstrated that ursodeoxycholic acid (UDCA) can close the ACE2 receptor, which is equivalent to closing the door
for the virus to enter cells.
Can the concept of "new crown miracle drug" ursodeoxycholic acid set off a new round of research and development?
Can the concept of "new crown miracle drug" ursodeoxycholic acid set off a new round of research and development?Global FXR modulator market development
Global FXR modulator market developmentFXR (Farnesol X Receptor) is a popular target for research in non-alcoholic fatty liver disease (NAFLD) in recent years
.
FXR is a member of the nuclear receptor superfamily, which was discovered by Forman et al.
in 1995, named because its transcriptional activity can be enhanced by farnesol and its metabolites, and later found that bile acids are endogenous ligands of FXR, so FXR is also called bile acid receptor (Bile
acid receptor，NR1H4）
。
After investigation, FXR regulators are mainly marketed and under research as shown
in Table 1.
Among them, only ursodeoxycholic acid and clinical phase 1 SIPI-7623 are FXR inhibitors (antagonists).
Given that the above study found that FXR inhibitors can downregulate ACE2 expression to prevent new crown, other FXR agonists are not under investigation
.
Table 1 FXR modulators are mainly marketed as drug candidates
Table 1
Source: Pharmacat Consulting
What is the domestic ursodeoxycholic acid market?
What is the domestic ursodeoxycholic acid market?Ursodeoxycholic
acid, UDCA) is a natural hydrophilic bile acid derived from cholesterol, which can reduce the saturation of cholesterol by inhibiting cholesterol reabsorption in the intestine and reducing the secretion of cholesterol into bile, and is clinically mainly used for the treatment
of cholelithiasis, cholestatic liver disease, cholereflux gastritis, primary sclerosing cholangitis, etc.
Ursodeoxycholic acid can be isolated from bear bile (bear bile, bear bile powder), or it can be produced
by chemical synthesis of chenodeoxycholic acid, porcine bile salt or porcine bile.
Limited by the scarcity and high cost of upstream bear bile resources, at present, ursodeoxycholic acid chemical raw materials are mostly synthesized by chemical methods to produce ursodeoxycholic acid chemical preparations.
Bear bile powder containing ursodeoxycholic acid is used to produce various proprietary Chinese medicines
for the purpose of clearing heat and detoxifying the liver.
After investigation, the domestic sales of ursodeoxycholic acid chemical preparations (hospital end) are shown in Figure 1, of which the sales of German Hawker Pharmaceutical (Dr.
Falk) account for the highest proportion, the main product is ursodeoxycholic acid capsules, which is the main downstream enterprise
of chemical synthesis of ursodeoxycholic acid.
Falk) has the highest share of sales
Figure 1 Domestic sales of ursodeoxycholic acid preparations (hospital, 100 million yuan)
Figure 1Image source: PharmaSmart Data, PharmaIntelligence Consulting
The consumption of bear bile powder in domestic bear bile powder-related traditional Chinese medicine preparations is shown in Table 2, of which Shanghai Kaibao Pharmaceutical's product bear bile powder consumption is the highest, the main products are sputum heat clear injection and sputum heat clear capsule, which is the main downstream enterprise
of bear bile powder.
Table 2 Consumption of bear bile powder in domestic traditional Chinese medicine preparations related to bear bile powder (hospital + retail, tons)
Table 2
Source: PharmaIntelligence
Status of research and development of new crown treatment drugs
Status of research and development of new crown treatment drugsAt present, the world mainly adopts vaccine prevention for new crown pneumonia, and the specific drugs that have been marketed mainly include:
(1) Small molecule drugs: (1) remdesivir (Gilead's original research, which was launched in Europe as early as July 2020, has been approved for marketing in more than 50 countries, but has not yet been approved in China); (2) Menapigravir (original research of Merck, listed in the UK as early as November 2021, but not yet approved in China); (3) Paxlovid (nematevir/ritonavir, original research of Pfizer, listed in the United States as early as December 2021, with conditional approval in China)
(1) Small molecule drugs(2) Combination therapy: (1) Neutralizing antibody drugs: ambavirumab/romisivimab combination therapy; (2) Bamlanivimab/Etesevimab combination therapy; (3) Casirivimab/Imdevimab combination therapy
.
Compared with neutralizing antibody drugs, small molecule chemical drugs have great advantages
in economy, convenience and accessibility.
The principle of action of chemical drugs focuses on inhibiting the replication process of the virus, preventing the virus from entering cells and inhibiting the inflammatory response of the human body, etc.
, which is not affected by virus mutation, is not easy to produce drug resistance, and can be used for the treatment
of light, medium and severe diseases of the new crown.
in economy, convenience and accessibility.
Affected by the mutation of the new crown virus strain, the proportion of new crown positive patients suffering from pneumonia and severe disease has dropped significantly compared with the early stage of the epidemic, and most of the above respiratory infections are currently the main ones, and the clinical and household medicines of patients are mainly symptomatic cold medicines and other auxiliary therapies
.
Ursodeoxycholic acid development prospects
Ursodeoxycholic acid development prospectsThe new crown drug has triggered the pursuit of the capital market
.
With the optimization of domestic epidemic prevention measures, drugs related to the prevention and treatment of new crown infection continue to attract attention
.
In the capital market, concepts such as new crown testing, ursodeoxycholic acid, and new crown specific drugs have also recently sparked a boom
.
In particular, the concept of ursodeoxycholic acid, due to the continuous fermentation of the aforementioned paper findings, continues to promote the heating up of the secondary market, and both investors and upstream and downstream enterprises in related industries are looking forward
to its future prospects.
.
There are still significant uncertainties
about the use of ursodeoxycholic acid for the prevention of the new crown.
Although ursodeoxycholic acid has been used clinically for many years, its safety and tolerability are good, and relevant studies have proved that it may have some efficacy in the prevention of the new crown, this is only in the early stages of research, and no confirmatory clinical trials
have been conducted.
about the use of ursodeoxycholic acid for the prevention of the new crown.
Lu Hongzhou, president of Shenzhen Third People's Hospital, said in an interview with the "Daily Economic News" reporter: "From a virological point of view, ursodeoxycholic acid may be effective
.
The spike protein is the key, and the ACE2 receptor is the lock, there are many such locks on the surface of human cells, and the function of ursodeoxycholic acid is to reduce the number of such locks on cells, but it does not completely remove the corresponding locks
.
From the perspective of preventing or treating the disease, it is too early
to evaluate whether ursodeoxycholic acid is effective as a drug to prevent the new crown.
”
Similarly, virology expert Chang Rongshan also said in an interview with the "Daily Economic News" reporter: "According to the experiments carried out in the paper, ursodeoxycholic acid can reduce the expression
of ACE2 in human lung cells.
However, the ACE2 expressed by human lung cells is relatively low, and many cells in the human body have ACE2 on the surface, which means that even if ACE2 in lung cells drops by 90%, it does not make much sense
.
In addition to ACE2 receptors, there are at least three or four receptor proteins of the new coronavirus on the surface of human cells, which can bind to the new coronavirus and make it enter human cells; Even if the ACE2 receptor is completely blocked, the new coronavirus still has a viral receptor
that enters human cells.
Omicron mainly infects the epithelial cells in the human nasal cavity, not lung cells, and from this point of view, ursodeoxycholic acid is not good to prevent new crown infection
.
”
In addition, Lu Hongzhou believes that "ursodeoxycholic acid can not shut down ACE2 receptors, at present, there are not many chemical drugs that can completely shut down molecular signaling pathways in the human body, because once a certain signaling pathway is completely closed in the human body, it will bring a devastating blow.
"
Chang Rongshan believes: "ACE2 is too important for the human body, it is not feasible to seal the road of ACE2, and there is currently a drug development direction for the host itself, that is, to enhance the immunity of our human body
.
" Most of the severe disease and death caused by new coronavirus infection is due to the cytokine storm, so as long as the cytokine storm after human infection is reduced, severe disease and death
can be reduced.
This R&D direction has been ongoing, but there is not much progress so far; Because there are few severe diseases now, even if the drug is successfully developed, the market will not be too large
.
”
The above two experts said that whether it is new drug development or overdose use of existing drugs, this system needs to be followed to ensure the safety and efficacy
of drugs.
It is not recommended that healthy people take ursodeoxycholic acid to prevent new coronavirus infection, even for high-risk groups, such as medical personnel and consumer site practitioners, it needs to be used
with caution.
Eating ursodeoxycholic acid in healthy people is risky and will cause side effects
to the human body.
ACE2 is a very important protein molecule in the human body that lowers blood pressure
.
If you take ursodeoxycholic acid for a long time, instead of taking the medicine according to a prescription, there are some potential risks
.
brief summary
brief summaryThe key to the repercussions caused by ursodeoxycholic acid is that the research results in Nature provide a new idea: as an RNA virus, the new coronavirus mutates rapidly, and drug research and development always lags behind mutation; By controlling the entrance of the virus into the human body, directly guarding the enemy from the outside, the problem
caused by virus mutation will be fully avoided.
During the epidemic, the market effect brought by masks, new crown vaccines, diagnostic reagents, cold medicines, etc.
was too huge, making ursodeoxycholic acid, which also has the potential to prevent new crown infection, attracted the market
.
But most of the "imminent moves" are capital markets catching the wind and pushing the tide
.
Based on the current findings, the development of ursodeoxycholic acid as a new crown specific drug or preventive drug, efficacy verification and marketing development still has a long way to go, and there is great uncertainty
.
At the same time, given that the current new crown patients are mainly mild, and their treatment drugs are mainly conventional symptomatic treatment, how many companies will still die on the extremely difficult road of "new crown special drugs"? We will wait and see
the development of relevant drugs in the post-epidemic era.
