CN114146090A - New application of apilimod as coronavirus broad-spectrum inhibitor - Google Patents

New application of apilimod as coronavirus broad-spectrum inhibitor Download PDF

Info

Publication number
CN114146090A
CN114146090A CN202010915364.8A CN202010915364A CN114146090A CN 114146090 A CN114146090 A CN 114146090A CN 202010915364 A CN202010915364 A CN 202010915364A CN 114146090 A CN114146090 A CN 114146090A
Authority
CN
China
Prior art keywords
coronavirus
apilimod
virus
pneumonia
sars
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
Application number
CN202010915364.8A
Other languages
Chinese (zh)
Inventor
徐欢
童贻刚
范华昊
宋立华
周美玲
安小平
葛琳
刘艳玲
洪碧霞
翟丽丽
陈杨桢
郑海洲
魏敬双
朱秀良
高健
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
North China Pharmaceutical New Drug R&d Co ltd
Beijing University of Chemical Technology
Original Assignee
North China Pharmaceutical New Drug R&d Co ltd
Beijing University of Chemical Technology
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by North China Pharmaceutical New Drug R&d Co ltd, Beijing University of Chemical Technology filed Critical North China Pharmaceutical New Drug R&d Co ltd
Priority to CN202010915364.8A priority Critical patent/CN114146090A/en
Publication of CN114146090A publication Critical patent/CN114146090A/en
Pending legal-status Critical Current

Links

Images

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Virology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The invention discloses a new application of apilimod, wherein apilimod is used as a broad-spectrum inhibitor of coronavirus for treating 2019 novel coronavirus, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) pneumonia infection and common cold caused by human coronavirus OC43(HCoV-OC 43). Apilimod can bind to spike protein S1 of coronavirus, affecting the virus-binding receptor, thereby blocking the virus from entering cells. The apilimod is used as a new old medicine, has no problem on the safety, and therefore can be applied to clinic.

Description

New application of apilimod as coronavirus broad-spectrum inhibitor
Technical Field
The invention belongs to the field of medicines, relates to a new application of apilimod, and particularly relates to an application of apilimod in treatment of coronavirus infection.
Background
Highly pathogenic coronavirus infection has become a public health concern over the last decade. Severe acute respiratory syndrome (SARS, 2002-2004), middle east respiratory syndrome (MERS, 2012-to-date), 2019 novel coronavirus 2019-nCoV (COVID-19), each of which has a tremendous impact on human health and economic development.
Because there are no effective drugs and vaccines, the research and development of new drugs for new coronavirus is of great significance, and in the war without smoke, a plurality of scientific research institutions and pharmaceutical companies around the world are dedicated to research and develop new coronavirus vaccines and therapeutic drugs. The invention in the field has great social and economic significance.
Apilimod, apilimimod, is a small molecule compound with cell permeability that inhibits PIKfyve with an IC50 of 14nM, for the treatment of autoimmune diseases such as crohn's disease. It is also an IL-12/23 inhibitor and is inactive against other lipid kinases and protein kinases such as PIP4K, PIP5K, mTOR, PI3K and PI4K subtypes.
Disclosure of Invention
The invention aims to provide an effective inhibitor of coronavirus including 2019 novel coronavirus (COVID-19), and can prevent and treat coronavirus infection including 2019 novel coronavirus. The invention provides a new application of apilimod, which is an effective inhibitor of coronavirus including 2019 novel coronavirus, and an application of the apilimod in preparation of a medicament for preventing or treating coronavirus infection.
The application is that the coronavirus comprises 2019 novel coronavirus (COVID-19), Severe Acute Respiratory Syndrome (SARS) virus, Middle East Respiratory Syndrome (MERS) virus, common cold human coronavirus OC43(HCoV-OC43), human coronavirus NL63(HCoV-NL63), human coronavirus 229E (HCoV-229E) and human coronavirus HKU1(HCoV-HKU 1).
The application, wherein the coronavirus is 2019 novel coronavirus (COVID-19).
The use wherein the coronavirus infection is coronavirus pneumonia or common cold.
The application is characterized in that the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS, middle east respiratory syndrome MERS, human coronavirus OC43 pneumonia, human coronavirus NL63 pneumonia, human coronavirus 229E pneumonia, human coronavirus HKU1 pneumonia and common cold.
The use of (b), wherein the coronavirus infection is 2019 novel coronavirus pneumonia.
The inventors have found a new use of apilimod through a great deal of research, wherein apilimod can bind 2019 spike protein S1 of a novel coronavirus, so as to block the virus from entering cells, and the apilimod is EC 50-86 nM, CC 50-47.39 uM, and SI-551 at the cellular level.
2019 the novel coronavirus enters the cell and recognizes the receptor ACE2 by the spike protein spike, so that the small molecule inhibitor taking the spike protein as a target can be applied to the treatment of the novel coronavirus.
The inventors also found that apilimod binds equally well to the S1 target protein of SARS and MERS. Therefore, apilimod can be applied to the treatment of the coronavirus infection of the subtypes.
The compounds of the present invention may be formulated into various suitable pharmaceutical preparation forms. Can be used alone or mixed with medicinal adjuvants (such as excipient, diluent, etc.) to make into oral tablet, capsule, granule or syrup, or powder for injection or solution.
Compared with the prior art, the invention has the following technical effects:
apilimod can bind with spike protein S1 at cellular level, prevent virus from entering cells, and treat coronavirus pneumonia infection and common cold, and inhibit EC50 of GX-P2V coronavirus to 86 nM.
The inventor finds that the apilimod can not inhibit vesicular stomatitis virus VSV, and proves that the apilimod can inhibit coronavirus and Spike protein Spike are related.
Drawings
FIG. 1 prediction of SARS-CoV-2S 1& apilimod binding site
Figure 1 shows AI predicted binding sites for apilimod and 2019 novel coronavirus S1 protein.
FIG. 2 prediction of SARS-CoV S1& apilimod binding site
FIG. 2 shows AI-predicted binding sites for apilimod and SARS coronavirus S1 proteins.
FIG. 3 prediction of MERS-CoV S1& apilimod binding site
Fig. 3 shows AI predicted binding sites for apilimod and MERS coronavirus S1 proteins.
FIG. 4 SARS-CoV-2S 1& apilimod sensorgram
Figure 4 shows the affinity of apilimod and 2019 novel coronavirus S1 protein.
FIG. 5 SARS S1& apilimod sensorgram
Figure 5 shows the affinity of apilimod and SARS virus S1 protein.
FIG. 6, MERS S S1+ S2 ECD & apilimod sensing diagram
Figure 6 shows the affinity of apilimod and MERS virus S1+ S2 ECD proteins.
FIG. 7, OC 43S 1+ S2 ECD & apilimod sensing diagram
Figure 7 shows the affinity of apilimod and OC43 virus S1+ S2 ECD proteins.
FIG. 8, NL 63S 1+ S2 ECD & apilimod sensorgram
Figure 8 shows the affinity of apilimod and NL-63 virus S1+ S2 ECD proteins.
FIG. 9, HKU-1S1+ S2 ECD & apilimod sensorgram
FIG. 9 shows the affinity of apilimod and HKU-1 virus S1+ S2 ECD proteins.
FIG. 10. apilimod inhibits SARS-CoV-2 pseudovirus entry into cells
FIG. 11, the inhibition of SARS-CoV pseudovirus entry into cells by apilimod
FIG. 12. EC of apilimod in inhibiting MERS-CoV virus50
FIG. 13 EC of apilimod in inhibiting NL63-CoV Virus50
FIG. 14, the EC of apilimod for inhibiting GX-P2V virus50And CC50
FIG. 15. the inability of apilimod to inhibit VSV Virus
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The technical scheme of the present invention will be further described below with reference to specific experimental operations and data.
The inhibitory effect of apilimod on various subtypes of coronavirus is demonstrated by the following experiments. Sources of apilimod: purchased from selechchemicals, cat # S (S6414).
Example 1AI predicted binding site
The SARS-CoV-2spike protein (PDB: 6vw1) was downloaded from PDB (http:// www.rcsb.org /); SARS spike protein (pdb: 2dd 8); MERS spike protein (pdb: 6c6 z). All foreign atoms and spike ligands are removed. The Mpro docking grid is maximized for apilimod docking. The PDB file is converted to macromolecules in the PDBQT format prior to virtual screening. The position of the grid (ligand docking search space) is as described above. Then, Autodock Vina 1.1.2 was used for subsequent molecular docking. Using Pymol version 1.7.4.5 it was possible to observe protein binding toThe interaction of the ligands. spike protein proximity hit ligands
Figure BDA0002671131590000031
Are highlighted as potential interaction residues involved in protein-ligand interactions. The results are shown in FIGS. 1-3.
The experimental results are as follows:
the binding sites of apimod and SARS-CoV-2spike protein are VAL341, ALA344, PHE347, ALA348, SER349, TRP353, ASN354, ARG355, SER 399.
Binding sites of apilimo and SARS-CoV spike protein are PHE325, GLY326, PHE329, ASN330, ASP351, VAL354, LEU355, SER358, PHE 360.
Binding sites of apilimo and MERS-CoV spike protein are LYS502, SER504, PHE506, GLU513, PRO515, TYR540, VAL 555.
Example 2 coronavirus S protein SPR experiment
Experimental materials and instruments
biacore T200(GE healthcare, Uppsala, Sweden), CM5 chip (GE healthcare, Uppsala, Sweden), apilimod (select chemicals), 2019-CoV S1 protein (yinqian), SARS S1 protein (yinqian), MERS S1+ S2 ECD protein (yinqian), OC 43S 1+ S2 ECD protein (yinqian), NL 63S 1+ S2 ECD protein (yinqian), HKU-1S1+ S2 ECD protein (yinqian).
Model is biacore T200 of GE company, and S1 protein (Yiqian Shenzhou), SARS virus S protein (Yiqian Shenzhou), MERS virus S1+ S2 ECD protein (Yiqian Shenzhou), OC 43S 1+ S2 ECD protein (Yiqian Shenzhou), NL 63S 1+ S2 ECD protein (Yiqian Shenzhou), HKU-1S1+ S2 ECD protein (Yiqian Shenzhou) are coupled to a CM5 chip through amino groups, the coupling amounts are 9499.3RU,13628.8RU 14187.7RU,6082.3RU,14602.8RU,16061.2RU, and the affinities of the apilimod and the S protein at 25 ℃ are measured. Apilimod was injected at a flow rate of 30 μ L/min at concentrations of 100uM,50uM,25uM,12.5uM,6.25uM,3.125uM, 1.5625uM,0.78125uM,0uM for a sample injection time of 180s and a dissociation time of 300 s. The data analysis mode is steady state analysis. The results are shown in FIGS. 4-9. The SPR results are summarized in table 1 below.
TABLE 1 affinity of apilimod for binding to the S protein of various subtypes of coronavirus at 25 ℃
Protein KD(M) Rmax(RU) Chi2(RU2) chi
2019CoV S1 2.739*10-6 19.4 3.32 1.82
SARS S1 3.22*10-5 42.63 0.813 0.901
MERS S1+S2 1.029*10-4 129.8 3.43 1.85
OC43 S1+S2 9.829*10-5 76.31 2.19 1.48
NL63 S1+S2 7.497*10-5 119.3 9.04 3.01
HKU-1 S1+S2 7.155*10-6 46.98 3.76 1.94
Example 3
VSV-dG-fLuc replication-deficient pseudovirus infection experiment of coronavirus outer membrane-detection of Effect of apilimod in inhibiting coronavirus entry into cells
Experimental Material
VSV-dG-GFP, in which the glycoprotein (G) of VSV is replaced by GFP fluorescent protein. A pseudoviral packaging system for VSV-dG-fLuc (Firefo luciferase) Vesicular Stomatitis Virus (VSV) was obtained from reverse genetics plasmid rescue (Rescue), and the relevant plasmids were purchased from Karafast. Wherein pVSV- Δ G-Luciferase is used for transcription replication-deficient recombinant VSV genomes, wherein the glycoprotein (G) of VSV is replaced by Firefly Luciferase (fLuc), and pBS-N, pBS-P, pBS-L, pBS-G is used as an auxiliary vector to aid in first round of virus rescue.
Rescue and amplification of VSV-dG-fLuc replication-defective viruses containing the VSVG outer Membrane
BHK21 cells were attached to 3.5cm dish, and the next day when the cells reached 90% density, and infected with a poxvirus recombinantly expressing T7 RNA polymerase (Vaccinium virus-T7, vv-T7) at a titer of MOI ═ 5 (DMEM, serum-free) for 45 minutes at 37 ℃. After washing the cells once with PBS, the cells that had been infected with vv-T7 were transfected with the mixed reverse genetics plasmid (pVSV-. DELTA.G-Luciferase: pBS-N: pBS-P: pBS-G: pBS-L ═ 5:3:5:8:1) transfected with Lipo3000, the solution was changed after 12 hours, the supernatant containing the primary VSV-dG-fLuc virus was collected after 48 hours, and the residual vv-T7 was removed by filtration through a 0.22 μm filter. To further amplify the virus, HEK293T cells were transfected with pMD2.G overexpressing VSV G protein (ATCC: Plasmid #12259), 24 hours later, primary supernatants were combined with DMEM + 10% serum 1: 1 for infection, collecting the supernatant after 24-48 hours, centrifuging at 12000 rpm for 2 minutes, retaining the supernatant and packaging, determining the virus titer by plaque method, and storing at-80 ℃.
Packaging VSV-dG-fLuc replication-deficient pseudovirus containing coronavirus SARS-CoV-2, SARS-CoV, MERS-CoV, NL63-CoV outer membrane
HEK293T cells or Vero-E6 cells were transfected with plasmids overexpressing the SARS-CoV-2, SARS-CoV, MERS-CoV, NL63-CoV outer membrane proteins (pCAGGS-SARS-2-S-dc) (pCAGGS-SARS-S-dc). After 24 hours, the transfected cells were infected with VSV-dG-ffluc virus containing the VSVG outer membrane at MOI ═ 10 (1:30 dilution) for 1 hour at 37 ℃, followed by addition of a solution containing 1: DMEM + 10% FBS medium with 300 dilutions of rat anti-VSVG antiserum was used to completely neutralize residual VSV-dG-fLuc pseudovirus containing the VSVG outer membrane. The virus-containing supernatants were harvested after 24-48 hours, centrifuged at 12000 rpm for 2 minutes, retained and aliquoted, assayed for viral titer by CPE using limiting dilution (Infections Unit) and stored at-80 ℃.
Determination of half effective depth of drug by infection with SARS-CoV-2, SARS-CoV, MERS-CoV and NL63-CoV pseudoviruses based on VSV (EC50)
BHK21-ACE2 cells (Wuhan Dai selection) were attached to 96-well plates. After 24 hours, the cell density reached about 90%, and different concentrations of the drug were mixed with different pseudoviruses, such as VSV-dG pseudovirus expressing GFP or Fluc containing VSVG outer membrane protein or SARS-CoV-2/SARS-CoV/MERS-CoV outer membrane protein (MOI ═ 0.1), respectively, in a DMEM + 10% FBS medium, and then the cells were infected. After 24 hours, cells expressing GFP after infection were photographed by fluorescence microscopy; or to measure intracellular fluoresceinEnzyme intensity, the culture supernatant was removed, 20. mu.l of 1 XPassive lysine buffer (Promega) was added, and the mixture was left at room temperature for 10 minutes and passed through One-Glo luciferase kit (Promega) and
Figure BDA0002671131590000063
20/20 bioluminescence assay apparatus (Promega). Cytotoxicity was observed by microscopic bright field. The results are shown in FIGS. 10-13.
Example 4GX-P2V coronavirus infection assay to examine the Effect of apilimod on inhibiting coronavirus replication
The detection principle is that GX-P2V is highly homologous with SARS-CoV-2, and the comparison analysis of the whole genome and each virus coding gene (nucleotide level and amino acid level) shows that: GX-P2V is highly homologous with SARS-CoV-2, the homology with S protein of SARS-CoV-2 is 92.5%, it is the virus which has the highest homology with S protein of SARS-CoV-2 and is successfully isolated and cultured so far, no matter it is whole genome level or the key gene S gene of virus adsorbed into cell, the homology of GX P2V and SARS-CoV-2 is far higher than SARS virus, see Table 2.
TABLE 2GX P2V comparison of nucleic acid and amino acid homologies with other coronaviruses
Figure BDA0002671131590000061
#Wuhan-Hu-1 SARS-CoV-2(NC_045512.2)was used for comparison with Bat-Cov Ra TG13(EPI_ISL_402132),Guangdong pangolin Cov(merged of GD/PIL and GD/P2S),and Guangxi pangolinCoV(GX/P5L)
partial sequence
A substitution model of 2019-nCoV is used, so that the risk and the complexity of operating experiments in a P3 laboratory are avoided. The GX P2V virus used by the people can be cultured in a common P2 laboratory, can be used as an ideal anti-2019-nCoV virus substitution model, and a large number of basic experiments can be verified by the 2019-nCoV virus after being explored on the virus model.
Experimental materials and instruments:
cell: vero E6, manufacturer ATCC
Virus: GX-P2V virus, North chemical industry of manufacturers
Sample preparation: aripimod, vendor select chemicals, concentration 10mM, storage conditions-20 degrees
Detection reagent:
TABLE 3 detection reagents
Figure BDA0002671131590000062
Figure BDA0002671131590000071
EC50 and CC50 studies on inhibition of GX-P2V by apilimod
1) Culture of cells
Vero E6 cells (ATCC) were cultured with high-glucose DMEM + 10% fetal bovine serum. Cells were cultured at 1.5X104Density of/well was seeded in 96-well plates (Thermo Fisher) or 8X104Density per well was inoculated into 24-well plates and incubated at 37 ℃ in a 5% CO2 incubator.
2) Determination of semi-effective concentration EC50 of apilimod
Vero E6 cells were seeded into 24-well plates, the next day, the cells were infected with GX-P2V virus and 2-fold dilutions of the compound (100 uM max) were added, after 2h the supernatant was aspirated off and washed with PBS buffer, followed by 2-fold dilutions of the drug (100 uM max). 37 ℃ and 5% CO2The incubator was incubated for 72 hours. QRT-PCR was used to detect viral copy number. The value of EC50 was determined using non-linear regression.
3) Confirmation of EC50 and CC50 of apilimod inhibiting GX-P2V
Vero E6 cells were seeded into 24-well plates, and the next day, 0.195,0.39,0.78,1.56,3.12,6.24,12.5,25,5 and 100. mu.M apilimod was added to the cells, respectively, followed by the virus. After 2 hours, the supernatant was removed by changing the solution, and washed with PBS buffer to remove virus particles that did not enter the cells, and then the cells were added with apilimod again at 0.195,0.39,0.78,1.56,3.12,6.24,12.5,25,5 and 100 μ M. The copy number of the viral RNA in the cells was quantified by qRT-PCR 72h after viral infection and normalized with GAPDH levels. The cytotoxicity of the drug to vero E6 was measured using the CellTiter-Blue Activity assay.
The result is shown in figure 14, the low-concentration apilimod can obviously inhibit GX-P2V, and the EC50, CC50 and SI of the apilimod on GX-P2V are 86nM, 47.39 mu M and 551 respectively, and the data show that the apilimod has good effect on resisting coronavirus GX P2V and has potential for clinically treating coronavirus infection.
Example 5
Apilimod cannot inhibit vesicular stomatitis virus VSV, demonstrating that apilimod inhibition of coronavirus is associated with Spike protein Spike. See fig. 15.

Claims (10)

1. Application of apilimod in preparing medicine for preventing and treating coronavirus infection.
2. Use according to claim 1, characterized in that: the coronavirus comprises 2019 novel coronavirus COVID-19, severe acute respiratory syndrome SARS virus, middle east respiratory syndrome MERS virus, human coronavirus HCoV-OC43, human coronavirus NL63, human coronavirus 229E and human coronavirus HKU 1.
3. Use according to claim 1, characterized in that: the coronavirus includes 2019 novel coronavirus COVID-19, severe acute respiratory syndrome SARS virus and middle east respiratory syndrome MERS virus.
4. Use according to claim 1, characterized in that: the coronavirus is a 2019 novel coronavirus COVID-19.
5. Use according to any one of claims 1 to 4, characterized in that: the coronavirus infection is coronavirus pneumonia or common cold.
6. Use according to any one of claims 1-2, characterized in that: the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS, middle east respiratory syndrome MERS, human coronavirus HCoV-OC43 pneumonia, human coronavirus NL63 pneumonia, human coronavirus 229E pneumonia, human coronavirus HKU1 pneumonia and common cold.
7. Use according to any one of claims 1 to 3, characterized in that: the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS and middle east respiratory syndrome MERS.
8. Use according to any one of claims 1 to 4, characterized in that: the coronavirus infection is 2019 novel coronavirus COVID-19 pneumonia.
9. Use according to any one of claims 1 to 4, characterized in that: apilimod binds to spike protein S1 of coronavirus.
10. Use according to claim 1, characterized in that: when in use, the oral preparation is adopted, and the oral preparation contains the apilimod with effective treatment amount and pharmaceutically acceptable carrier auxiliary materials for preparing the oral preparation.
CN202010915364.8A 2020-09-08 2020-09-08 New application of apilimod as coronavirus broad-spectrum inhibitor Pending CN114146090A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202010915364.8A CN114146090A (en) 2020-09-08 2020-09-08 New application of apilimod as coronavirus broad-spectrum inhibitor

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202010915364.8A CN114146090A (en) 2020-09-08 2020-09-08 New application of apilimod as coronavirus broad-spectrum inhibitor

Publications (1)

Publication Number Publication Date
CN114146090A true CN114146090A (en) 2022-03-08

Family

ID=80460189

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202010915364.8A Pending CN114146090A (en) 2020-09-08 2020-09-08 New application of apilimod as coronavirus broad-spectrum inhibitor

Country Status (1)

Country Link
CN (1) CN114146090A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111759841A (en) * 2020-06-03 2020-10-13 山西第三医学研究发展有限公司 Application of pidotimod in resisting novel coronavirus infection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1460474A (en) * 2003-07-08 2003-12-10 中国医学科学院医药生物技术研究所 Application of geldanamycin in preparation of medicine for curing SARS
CN106074506A (en) * 2016-06-13 2016-11-09 广州医科大学附属第医院 The application that arbidol hydrochloride prevents in preparation and treats in the medicine of anti-Middle East respiratory system syndrome coronavirus
CN111544442A (en) * 2020-06-02 2020-08-18 华北制药集团新药研究开发有限责任公司 New use of rutin as coronavirus broad-spectrum inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1460474A (en) * 2003-07-08 2003-12-10 中国医学科学院医药生物技术研究所 Application of geldanamycin in preparation of medicine for curing SARS
CN106074506A (en) * 2016-06-13 2016-11-09 广州医科大学附属第医院 The application that arbidol hydrochloride prevents in preparation and treats in the medicine of anti-Middle East respiratory system syndrome coronavirus
CN111544442A (en) * 2020-06-02 2020-08-18 华北制药集团新药研究开发有限责任公司 New use of rutin as coronavirus broad-spectrum inhibitor

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUAN-LIN KANG ET AL.: "Inhibition of PIKfyve kinase prevents infection by Zaire ebolavirus and SARS-CoV-2", 《PNAS》, 25 August 2020 (2020-08-25), pages 20803 - 20813, XP055801336, DOI: 10.1073/pnas.2007837117 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111759841A (en) * 2020-06-03 2020-10-13 山西第三医学研究发展有限公司 Application of pidotimod in resisting novel coronavirus infection

Similar Documents

Publication Publication Date Title
Boopathi et al. Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment
Zhang et al. Understanding the role of SARS-CoV-2 ORF3a in viral pathogenesis and COVID-19
Larue et al. Rationally designed ACE2-derived peptides inhibit SARS-CoV-2
Musarrat et al. The anti‐HIV drug nelfinavir mesylate (Viracept) is a potent inhibitor of cell fusion caused by the SARSCoV‐2 spike (S) glycoprotein warranting further evaluation as an antiviral against COVID‐19 infections
Senapati et al. Contributions of human ACE2 and TMPRSS2 in determining host–pathogen interaction of COVID-19
Wu et al. Severe acute respiratory syndrome coronavirus 2: from gene structure to pathogenic mechanisms and potential therapy
Robinson et al. Predicting the next eye pathogen: analysis of a novel adenovirus
Yang et al. Inhibitory effect on SARS‐CoV‐2 infection of neferine by blocking Ca2+‐dependent membrane fusion
Yang et al. Drug repurposing of itraconazole and estradiol benzoate against COVID‐19 by blocking SARS‐CoV‐2 spike protein‐mediated membrane fusion
Saville et al. Three-dimensional visualization of viral structure, entry, and replication underlying the spread of SARS-CoV-2
Rosendal et al. Serine protease inhibitors restrict host susceptibility to SARS-CoV-2 infections
Han et al. Advances and challenges in the prevention and treatment of COVID-19
Wędrowska et al. Coronaviruses fusion with the membrane and entry to the host cell
Manhas et al. Covid-19 pandemic and current medical interventions
Hashizume et al. Phenothiazines inhibit SARS-CoV-2 cell entry via a blockade of spike protein binding to neuropilin-1
Kumar et al. A review of novel coronavirus disease (COVID-19): based on genomic structure, phylogeny, current shreds of evidence, candidate vaccines, and drug repurposing
Gong et al. COVID-19: A state of art on immunological responses, mutations, and treatment modalities in riposte
Wang et al. Human endeavor for anti-SARS-CoV-2 pharmacotherapy: a major strategy to fight the pandemic
Wang et al. Recent progress of surface plasmon resonance in the development of coronavirus disease-2019 drug candidates
Buchwald Developing small-molecule inhibitors of protein-protein interactions involved in viral entry as potential antivirals for COVID-19
Septisetyani et al. SARS-CoV-2 antibody neutralization assay platforms based on epitopes sources: Live virus, pseudovirus, and recombinant S glycoprotein RBD
CN114146090A (en) New application of apilimod as coronavirus broad-spectrum inhibitor
Gupta Progress in studies on structural and remedial aspects of newly born coronavirus, SARS-CoV-2
Raj et al. Current understanding on molecular drug targets and emerging treatment strategy for novel coronavirus-19
Ma et al. Teicoplanin derivatives block spike protein mediated viral entry as pan-SARS-CoV-2 inhibitors

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination