CN116785295A - Application of raltegravir in preparation of medicines for preventing and treating novel coronavirus infection - Google Patents
Application of raltegravir in preparation of medicines for preventing and treating novel coronavirus infection Download PDFInfo
- Publication number
- CN116785295A CN116785295A CN202310785941.XA CN202310785941A CN116785295A CN 116785295 A CN116785295 A CN 116785295A CN 202310785941 A CN202310785941 A CN 202310785941A CN 116785295 A CN116785295 A CN 116785295A
- Authority
- CN
- China
- Prior art keywords
- raltegravir
- novel coronavirus
- application
- coronavirus infection
- preventing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CZFFBEXEKNGXKS-UHFFFAOYSA-N raltegravir Chemical compound O1C(C)=NN=C1C(=O)NC(C)(C)C1=NC(C(=O)NCC=2C=CC(F)=CC=2)=C(O)C(=O)N1C CZFFBEXEKNGXKS-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960004742 raltegravir Drugs 0.000 title claims abstract description 24
- 208000001528 Coronaviridae Infections Diseases 0.000 title claims abstract description 16
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims description 3
- 229940079593 drug Drugs 0.000 title description 7
- 230000002265 prevention Effects 0.000 claims 7
- 150000001875 compounds Chemical class 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 238000005507 spraying Methods 0.000 claims 1
- 101000638154 Homo sapiens Transmembrane protease serine 2 Proteins 0.000 abstract description 15
- 102100031989 Transmembrane protease serine 2 Human genes 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 7
- 238000001514 detection method Methods 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 239000007853 buffer solution Substances 0.000 abstract 1
- 239000007850 fluorescent dye Substances 0.000 abstract 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 abstract 1
- 239000000243 solution Substances 0.000 abstract 1
- 241001678559 COVID-19 virus Species 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 229940096437 Protein S Drugs 0.000 description 3
- 101710198474 Spike protein Proteins 0.000 description 3
- 238000009509 drug development Methods 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- 208000025721 COVID-19 Diseases 0.000 description 2
- 241000711573 Coronaviridae Species 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 102000011931 Nucleoproteins Human genes 0.000 description 2
- 108010061100 Nucleoproteins Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- MQQNFDZXWVTQEH-UHFFFAOYSA-N nafamostat Chemical compound C1=CC(N=C(N)N)=CC=C1C(=O)OC1=CC=C(C=C(C=C2)C(N)=N)C2=C1 MQQNFDZXWVTQEH-UHFFFAOYSA-N 0.000 description 2
- 229950009865 nafamostat Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 230000003612 virological effect Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- LQSLBVXESNRILG-VDGAXYAQSA-N Boc-Gln-Ala-Arg-7-amino-4-methylcoumarin Chemical compound CC1=CC(=O)OC2=CC(NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)OC(C)(C)C)C)=CC=C21 LQSLBVXESNRILG-VDGAXYAQSA-N 0.000 description 1
- 101710091045 Envelope protein Proteins 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 241000127282 Middle East respiratory syndrome-related coronavirus Species 0.000 description 1
- 101710188315 Protein X Proteins 0.000 description 1
- 101000933967 Pseudomonas phage KPP25 Major capsid protein Proteins 0.000 description 1
- 241000315672 SARS coronavirus Species 0.000 description 1
- 208000037847 SARS-CoV-2-infection Diseases 0.000 description 1
- 201000003176 Severe Acute Respiratory Syndrome Diseases 0.000 description 1
- 101710172711 Structural protein Proteins 0.000 description 1
- 102100021696 Syncytin-1 Human genes 0.000 description 1
- 108010003533 Viral Envelope Proteins Proteins 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 241001493065 dsRNA viruses Species 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 210000004779 membrane envelope Anatomy 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Abstract
The invention relates to an application of raltegravir in a medicine for preventing and treating novel coronavirus infection, which belongs to the field of medicine application and is implemented by the following technical scheme: the raltegravir and the TMPRSS2 enzyme solution expressed and purified in the laboratory are incubated for 10 minutes at normal temperature, and then fluorogenic substrate buffer solution is added for detection, so that the raltegravir has a good inhibition effect on TMPRSS2, and a reference is provided for the application of the raltegravir to the treatment of novel coronavirus infection.
Description
Technical Field
The invention belongs to the field of medicine application, and in particular relates to application of raltegravir in a medicine for preventing and treating novel coronavirus infection.
Background
The pandemic of covd-19 caused by the RNA virus SARS-CoV-2 severely affects public health and economy worldwide. Worldwide, up to 46 minutes in 4 pm at the middle of europe, 12 months, 9 days, 2022, 643,875,406 confirmed cases, including 6,630,082 deaths, have been reported to the world health organization. Its transmission power is relatively strong, and the omnirange variety is still ubiquitous throughout china and the world. SARS-CoV-2 belongs to the genus coronavirus beta and has a membrane-like, circular or oval particle with a genome size of 29.9KB. It has five basic genes encoding various structural and non-structural proteins. The major structural proteins of viral particles include Spike protein (S), envelope protein (E), membrane protein (M) and nucleoprotein (N). The nucleoprotein (N) encapsulates the RNA genome to form a nucleocapsid, which is surrounded by the viral envelope (E). The spike protein (S) of SARS-CoV-2 is a critical protein for viral infection of host cells.
When SARS-CoV-2 invades the host cell, TMPRSS2 located on the cell membrane cleaves the S2' site of the S2 subunit of spike protein, exposing the fusion peptide and allowing the virus to enter the host cell. In animal models of SARS and MERS coronavirus infection, knockout of TMPRSS2 greatly reduced airway transmission. The TMPRSS2 inhibitor Nafamostat (Nafamostat) can effectively block SARS-CoV-2 infection of lung cells. Thus, TMPRSS2 is critical in viral invasion. It is therefore urgent to find inhibitors of TMPRSS2 that have fewer safety side effects.
Computer-aided drug design (CADD) has been increasingly used for new drug development to help expedite design and reduce the capital required for new drug development. In view of the high failure rate of new drug clinical studies, finding new indications for existing drugs has become an attractive strategy to minimize drug development costs. Thus, in this study, we screened the FDA database for the drug raltegravir which inhibits TMPRSS2 activity, thereby preventing SARS-CoV-2 from entering the cells, and providing a potential treatment for COVID-19.
Disclosure of Invention
The invention aims to provide application of raltegravir in medicines for preventing and treating novel coronavirus infection. Leigrevir (C) 20 H 21 FN 6 O 5 ) Can effectively inhibit the activity of TMPRSS2, thereby inhibiting the novel coronavirus from entering cells. The IC of the invention can be found by the detection of the in vitro enzyme inhibitor of Rategrevir to TMPRSS2 through the figure 1 50 The invention provides a basis for developing a novel drug taking TMPRSS2 as a target point and provides a reference for application of raltegravir to treatment of novel coronavirus infection at 67nmol/L.
The chemical structure of raltegravir is shown below:
drawings
FIG. 1 is a graph showing the inhibition of TMPRSS2 by various concentrations of raltegravir
Detailed Description
The raltegravir referred to in the examples below was purchased from Shanghai source leaf biotechnology limited; boc-Gln-Ala-Arg-AMC, referred to in the examples below, was purchased from Hangzhou peptide Biotechnology Inc.
The invention is further described in detail below by way of example only.
We added to 96-well plates 10. Mu.L of enzyme solution containing TMPRSS2 with 10. Mu.L of different concentrations of Rategrevir in NaCl solution (150 mM) at pH=7, incubated at room temperature for 10 min, 10. Mu.L of substrate buffer 10. Mu.LBoc-Gln-Ala-Arg-AMC (10. Mu.M) was added, and the whole system was incubated at room temperature for 50 min, and detection was performed on a microplate reader with excitation light and emission light wavelengths of 345nm and 445nm. The TMPRSS2 enzyme activity was calculated as:
percentage of enzyme activity (%) = (experimental group fluorescence value-negative control group fluorescence value)/(no drug group fluorescence value-negative control group fluorescence value) ×100%
As a result, the concentration at which the activity of Rategrevir against TMPRSS2 was inhibited by half was 67nmol/L.
The foregoing describes preferred embodiments of the present invention and other persons skilled in the art will readily appreciate that various modifications and changes can be made without departing from the spirit and scope of the present invention, as set forth in the appended claims.
Claims (6)
1. The application of raltegravir in the preparation of medicaments for preventing and treating novel coronavirus infection is provided.
2. The use of raltegravir in the prevention and treatment of novel coronavirus infections according to claim 1, characterized in that said raltegravir is used as a single ingredient in the prevention and treatment of novel coronavirus infections.
3. The use of raltegravir in the prevention and treatment of novel coronavirus infection as claimed in claim 1, characterized in that said raltegravir is used as a component in a compound medicament for the prevention and treatment of novel coronavirus infection.
4. The use of raltegravir in the prevention and treatment of novel coronavirus infections according to claim 1, characterized in that said raltegravir is administered orally.
5. The use of raltegravir in the prevention and treatment of novel coronavirus infections according to claim 1, characterized in that said raltegravir is used by injection.
6. The use of raltegravir in the prevention and treatment of novel coronavirus infections according to claim 1, characterized in that said raltegravir is used by inhalation with spraying.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310785941.XA CN116785295A (en) | 2023-06-29 | 2023-06-29 | Application of raltegravir in preparation of medicines for preventing and treating novel coronavirus infection |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310785941.XA CN116785295A (en) | 2023-06-29 | 2023-06-29 | Application of raltegravir in preparation of medicines for preventing and treating novel coronavirus infection |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116785295A true CN116785295A (en) | 2023-09-22 |
Family
ID=88041374
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202310785941.XA Pending CN116785295A (en) | 2023-06-29 | 2023-06-29 | Application of raltegravir in preparation of medicines for preventing and treating novel coronavirus infection |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116785295A (en) |
-
2023
- 2023-06-29 CN CN202310785941.XA patent/CN116785295A/en active Pending
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|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |