TW202218667A - Application of angiotensin converting enzyme inhibitors for the prevention and treatment of coronavirus disease 2019 - Google Patents

Abstract

An use of an angiotensin converting enzyme inhibitor - Fosinopril for prevention and treating pneumonia is provided.

Description

New use of angiotensin-converting enzyme inhibitor-for the prevention and treatment of severe special infectious pneumonia

The present invention provides a new use of an angiotensin-converting enzyme inhibitor in a medicine for treating pneumonia, especially the use of an angiotensin-converting enzyme inhibitor in a medicine for preventing and treating pneumonia caused by coronavirus.

Coronavirus is a ribonucleic acid virus (RNA virus) with high variability, which can easily lead to difficulties in research and treatment. In recent years, the coronavirus has brought many disasters around the world, seriously affecting the global economy and industrial structure, and even changing the way of life of human beings. Middle East Respiratory Syndrome (MERS) in 2012 and Severe Idiopathic Pneumonia (COVID-19) in 2019.

Among them, severe special infectious pneumonia (COVID-19) is the most serious. COVID-19 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which was first discovered at the end of 2019. It quickly broke out and spread on a large scale in countries around the world, affecting more than 180 countries and regions, accumulating more than 45 million confirmed cases and more than 1 million deaths, and the numbers are still increasing.

At present, there are no preventive vaccines and therapeutic drugs for COVID-19 in the world, and the development of new preventive vaccines or therapeutic drugs will take 2-5 years at the earliest before they have the opportunity to be practically applied to the clinic. Therefore, there is an urgent need to provide a drug that can be quickly and effectively applied to pneumonia caused by coronavirus.

Since severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been confirmed to infect host cells through angiotensin-converting enzyme type 2 (ACE2), generally ACE2 receptors are not sensitive to ACE inhibitors. The present disclosure unexpectedly found that angiotensin-converting enzyme inhibitor-fosinopril can specifically bind to the ACE2 receptor.

Therefore, the present invention provides the use of an angiotensin-converting enzyme inhibitor for the treatment of pneumonia. Wherein, the angiotensin-converting enzyme inhibitor can be fosinopril. Since fosinopril can specifically bind to the ACE2 receptor, it can reduce the virus infecting host cells through ACE2 in the host cells, so as to achieve preventive, ameliorating or therapeutic effects.

In the present disclosure, the use of an angiotensin-converting enzyme inhibitor is also provided, which is used for a drug that binds to angiotensin-converting enzyme type II (ACE2) receptors. Wherein, the angiotensin-converting enzyme inhibitor can be fosinopril.

In the present disclosure, the medicament may further include another active ingredient for treating pneumonia. The prevention, improvement or treatment effect can be further enhanced by the pharmaceutical composition comprising fosinopril and another active ingredient for treating pneumonia. The pharmaceutical composition may be a combination of fosinopril and another active ingredient for treating pneumonia, respectively, or may be a composition of fosinopril and another active ingredient for treating pneumonia.

In the present disclosure, the active ingredient for treating pneumonia may be an antiviral drug, another angiotensin-converting enzyme inhibitor, or a combination thereof, but the present disclosure is not limited to this, as long as the prevention, improvement or treatment of pneumonia can be achieved. The active ingredients can be used together with fosinopril. Preferably, the active ingredient for treating pneumonia will not react chemically with fosinopril, so as to avoid affecting or reducing the binding effect of fosinopril to the ACE2 receptor.

In the present disclosure, examples of the active ingredient for treating pneumonia may be Benazepril, Captopril, Enalapril, Lisinopril, Moxy Moexipril, Oseltamivir, Perindopril, Quinapril, Trandolapril, Remdesivir, or a combination thereof, However, this disclosure is not limited to this.

In the present disclosure, the pneumonia may be pneumonia caused by a coronavirus, such as Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) or Severe Special Infectious Pneumonia (Coronavirus). disease 2019, COVID-19), but this disclosure is not limited thereto. Preferably, the pneumonia is severe special infectious pneumonia (COVID-19).

In this disclosure, the term "treating" includes alleviating, alleviating, ameliorating, inhibiting, delaying, reducing, preventing or causing reversion of a disease, disorder, symptom or state. The term "prevention" includes reducing the risk of getting or contracting a disease, disorder, symptom or condition.

In the present disclosure, the drug can be administered by any suitable method, such as oral, parenteral, pulmonary, nasal, lingual, sublingual, lingual, buccal, rectal, or injection, etc., but the present disclosure is not limited thereto .

In the present disclosure, the medicament can be administered in any suitable effective dose, and it is understood that the effective dose will vary depending on the route of administration, the use of excipients, and the possibility of co-usage with other agents.

In the present disclosure, the drug may further include pharmaceutically acceptable excipients, emulsifiers, surfactants, dispersants, suspending agents, stabilizers, diluents, solvents, carriers, polymers, colorants, or sweeteners, or a combination of the above, but the present disclosure is not limited thereto.

The present disclosure finds that the angiotensin-converting enzyme inhibitor-fosinopril can specifically bind to the angiotensin-converting enzyme type II (ACE2) receptor, which can reduce the virus's entry into host cells through the ACE2 receptor. Infection, in order to facilitate the application of angiotensin-converting enzyme inhibitor-fosinopril in the preparation of medicines for treating pneumonia or the preparation of medicines combined with ACE2 receptors.

The following specific embodiments are used to illustrate the embodiments of the present invention, and the following specific embodiments should be construed as illustrative only, and do not limit the rest of the disclosure in any way. Those skilled in the art Other advantages and functions of the present invention can be readily understood from the content disclosed in this specification. The present invention can also be implemented or applied by other different specific embodiments, and various details in this specification can also be modified and changed for different viewpoints and applications without departing from the spirit of the invention.

Since the general ACE2 receptor is not sensitive to ACE inhibitors, in order to confirm that Fosinopril can specifically bind to the ACE2 receptor, the ACE activity test was used to measure the concentration of 0.001µg/ml, 0.01µg/ml, 0.1µg Fosinopril/ml, 1µg/ml and 10µg/ml were tested for its binding to ACE1 receptor and ACE2 receptor, respectively. In addition, the general ACE inhibitor-captopril (Captopril) is also taken as an example to test the binding of captopril to ACE1 receptor and ACE2 receptor respectively.

ACE activity test

Steps: Use the soluble somatic ACE enzyme activity (unit/microliter) in human serum to measure ACE activity; add human serum (4 units of ACE) and add a fixed concentration of the drug to be tested (captopril, Fosinopril), after adding a mixture of 400 mM boric acid (pH 8.3) and 300 mM sodium chloride, at 37°C for 20 minutes. Then add hippuryl-L-histidyl-L-leucine (HHL) to the mixed solution to a final reaction concentration of 2 mM, and mix The solution was incubated at 37°C for 2 hours, then NaOH was added to quench the reaction. The resulting product HL was labeled with ortho-phthalaldehyde (OPA), and the fluorescent product was measured using a fluorometer (Fluoroskan Ascent FL, Thermo Fisher, Waltham, MA, USA) with an excitation light wavelength of 355 nm and a scattered light wavelength of 355 nm. 535nm. By measuring the numerical value of the product, [1-(fluorescence intensity of blank/fluorescence intensity of inhibitor)]×100 corresponds to relative ACE inhibitory activity (%). IC50 indicates the inhibitor concentration required to achieve 50% inhibition .

The test results are shown in Figure 1 and Figure 2, in which Figure 1 is the concentration relationship diagram of fosinopril and captopril inhibiting ACE1 receptors respectively, Figure 2 is the inhibition of ACE2 by fosinopril and captopril respectively Receptor concentration graph.

From the results in Figures 1 and 2, 10 µg/ml of fosinopril can inhibit about 9% of ACE1 receptors and about 55% of ACE2 receptors. It is highly selective for ACE receptors. More specifically, fosinopril can specifically bind to ACE2 receptors, so it has a high potential to specifically inhibit ACE2 receptors.

In contrast to captopril, 10 µg/ml captopril can inhibit about 50% of ACE1 receptors, but only about 4% of ACE2 receptors. Here, the general insensitivity of ACE2 receptors to ACE inhibitors was also verified. Therefore, captopril cannot specifically bind to the ACE2 receptor.

Molecular simulation

The binding of fosinopril to the ACE2 receptor was further analyzed by molecular simulation technology, and the results are shown in FIG. 3 .

It can be found from Figure 3 that since the molecular structure of fosinopril is roughly consistent with the configuration of the ACE2 receptor, fosinopril can specifically bind to the predetermined position of the ACE2 receptor, thus showing high specificity. .

In conclusion, the present disclosure finds that the angiotensin-converting enzyme inhibitor-fosinopril can specifically bind to the angiotensin-converting enzyme type II (ACE2) receptor, and is expected to be applied in the treatment of pneumonia The use of the drug or the use of the drug that binds to the ACE2 receptor.

The above embodiments should be construed to be illustrative only and not to limit the remainder of the present disclosure in any way.

none

Figure 1 is a graph showing the concentration relationship of fosinopril and captopril respectively inhibiting ACE1 receptor. FIG. 2 is a graph showing the concentration relationship of fosinopril and captopril respectively inhibiting ACE2 receptors. Figure 3 is a schematic diagram of the binding of fosinopril to the ACE2 receptor.

Claims (7)

Use of an angiotensin-converting enzyme inhibitor for preparing a medicament for preventing and treating pneumonia. The use according to claim 1, wherein the angiotensin-converting enzyme inhibitor is Fosinopril. The use according to claim 1, wherein the medicament further comprises another active ingredient for treating pneumonia. The use according to claim 3, wherein the active ingredient for treating pneumonia is an antiviral drug, another angiotensin-converting enzyme inhibitor or a combination thereof. The use according to claim 3, wherein the active ingredient for treating pneumonia is Benazepril, Captopril, Enalapril, Lisinopril, Moexipril, Oseltamivir, Perindopril, Quinapril, Trandolapril, Remdesivir, or their combination. The use according to claim 1, wherein the pneumonia is pneumonia caused by a coronavirus. The use according to claim 6, wherein the pneumonia is severe special infectious pneumonia (COVID-19).

Images