CN115006395B - Application of XL888 in preparation of medicine for resisting adenovirus infection - Google Patents
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Abstract
The invention belongs to the technical field of biomedicine, and discloses application of XL888 in preparation of a medicament for resisting adenovirus infection, wherein the medicament for relieving and/or preventing and/or treating adenovirus infection acts by inhibiting the activity of adenovirus replication. The adenovirus is various adenovirus types including but not limited to AdV3 subtype, adV5 subtype. A medicament for the alleviation and/or prevention and/or treatment of adenoviral infection comprises XL888 and a pharmaceutically acceptable carrier. The invention provides application of a small molecular compound XL888 in preparation of a medicament for treating adenovirus infection, and provides a safe and effective small molecular compound for clinical treatment of adenovirus. XL888 can effectively inhibit replication of adenovirus in a nontoxic range, can be further developed into a medicament for treating diseases caused by adenovirus infection, and has wide application prospect.
Description
Technical Field
The invention belongs to the technical field of biomedicine, and particularly relates to application of XL888 in preparation of a medicament for resisting adenovirus infection.
Background
Currently, human adenoviruses (HAdV) belong to the genus mammalian adenoviruses of the family adenoviridae. Adenovirus is a nonenveloped icosahedral nucleocapsid DNA virus, the core of the viral genome is a linear double-stranded DNA molecule of about 36kb, and its genome is highly densely packed and organized into chromatin by hundreds of histone-like proteins VII and protamine-like proteins Mu (also known as protein X). The capsid of adenovirus has 240 hexon proteins (hexon) and the 12 apices of the icosahedral capsid are complexes of pentameric (penton) and trimeric (fiber) proteins. The 12 fiber proteins project from the capsid surface with the penton protein as the base, and the top of the fiber forms the knob region (knob). The knob region of the penton protein and the fiber protein can be combined with a virus receptor on the cell surface, and plays a very important role in the process of virus infection of cells. The smaller capsid proteins IIIa, VI, VIII and IX are embedded in the capsid, wherein capsid protein VI is located on the inner surface of the capsid and connects the capsid to the core comprising the viral genome via capsid protein V. Also a small amount of capsid protein IVa2 is involved in genome packaging and adenovirus protease (AVP) formation in the capsid.
Adenovirus infection can occur in any season, but often winter and early spring are the peak seasons of viral infection. Based on seroneutralization, hemagglutination epitopes, genomic sequence and function, human adenoviruses are divided into seven serotypes A, B, C, D, E, F and G, and the serotypes are 57. The types of adenovirus popular in China mainly include 1 type, 3 type, 4 type, 5 type, 7 type, 11 type, 14 type, 40 type, 41 type and 55 type, wherein adenovirus flow behaviors of 3 type and 5 type are dominant. It was found that various types of adenoviruses, except for the hexon, fiber, penton genes, are highly conserved in the genome and that intraspecies recombination rarely occurs. Therefore, the method is beneficial to overcoming the limitation of the specificity of the medicaments on the type of the adenovirus, and generally, the antiviral medicaments aiming at the later stage of the entry of the adenovirus have broad-spectrum anti-adenovirus activity in the adenovirus species.
Adenovirus infection has a variety of clinical symptoms and disease manifestations, which depend largely on the type of adenovirus, the immune status of the host and the site of infection. Common sites of infection with adenovirus include the respiratory tract, corneal epithelium and intestinal tract. 90% of the cases of viral conjunctivitis are caused by adenovirus infection, usually associated with adenovirus type B, D or E infections, and often appear in the form of pharyngeal conjunctivitis or Epidemic Keratoconjunctivitis (EKC) in the recruited recruits. B. Adenovirus type D or E also frequently causes acute respiratory diseases and viral pneumonia. Two of the more serious consequences of respiratory adenovirus infection are pneumonia, which can be fatal in children. And acute respiratory distress syndrome, which is more common in people who are eligible. Adenoviruses of the A, F and G types are associated with gastrointestinal infections. Adenovirus infection is the primary cause of gastroenteritis in children, second only to norovirus and rotavirus. In general, adenoviruses are susceptible to all populations, with more serious diseases and even death often occurring in infected newborns, children, and immunocompromised populations (hematopoietic stem cells and organ transplant patients).
There are currently no antiviral drugs approved for the treatment of adenoviral infections. Certain DNA/RNA synthesis inhibiting antiviral drugs approved for the treatment of other viral infections (e.g., cidofovir, ganciclovir, and ribavirin) have been used clinically to treat severe adenoviral infections by expanding the indications as trial drugs. However, most of these drugs have limited efficacy and severe adverse effects. Therefore, there is a need to develop other safer and more effective anti-adenovirus drugs.
XL888 is a potential novel therapeutic agent for treating melanoma, solid tumors and gastrointestinal cancer, is a novel and effective HSP90 inhibitor, and can inhibit proliferation of various human tumor cell lines. XL888 leads to the blockade of many key oncogenic pathways by inducing the degradation of the associated oncogenic client proteins in tumor cells, leading to tumor regression. However, no report is currently available on the treatment of adenoviral infections with XL 888.
Through the above analysis, the problems and defects of the prior art are as follows:
(1) There are no reports on XL888 for treating adenovirus infection.
(2) The prior art relates to a medicament for treating adenovirus infection, which has low drug effect and poor effect.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides the application of XL888 in preparing a medicament for resisting adenovirus infection.
The invention is realized by the application of XL888 in the preparation of medicines for relieving and/or preventing and/or treating adenovirus infection.
Further, XL888 has a structural formula as follows:
further, the adenovirus comprises adenovirus type B AdV3 subtype and adenovirus type C AdV5 subtype.
Further, the adenovirus is one or more of human adenovirus type 1, 3, 4, 5, 7, 11, 14, 40, 41 and 55.
Further, the medicament for alleviating and/or preventing and/or treating adenovirus infection acts by inhibiting the activity of adenovirus replication.
Further, the medicament for alleviating and/or preventing and/or treating adenovirus infection comprises XL888 and a pharmaceutically acceptable carrier.
Furthermore, the dosage form of the medicament for relieving and/or preventing and/or treating the adenovirus infection is any one clinically acceptable oral administration dosage form, injection administration dosage form or external administration dosage form.
Further, the medicine for relieving and/or preventing and/or treating the adenovirus infection is tablets, capsules, granules, oral liquid and injection.
The invention also aims to provide application of XL888 in preparation of an adenovirus inhibitor.
In combination with the above technical solutions and the technical problems to be solved, please analyze the advantages and positive effects of the technical solutions to be protected in the present invention from the following aspects:
aiming at the current situation that the prior art has no antiviral drug for adenovirus infection, the invention provides a novel anti-adenovirus drug-XL 888 by combining experimental data of low cytotoxicity of XL888 in Vero cells, high antiviral activity to two adenoviruses and the like in the research and development process, provides a new technology of the antiviral drug for adenovirus infection, and provides a brand new therapy and more treatment options for treating diseases caused by adenovirus infection.
The invention provides application of a small molecular compound XL888 in preparation of a medicament for treating adenovirus infection, and provides a safe and effective small molecular compound for clinical treatment of adenovirus. XL888 can effectively inhibit replication of adenovirus in a nontoxic range, can be further developed into a medicament for treating diseases caused by adenovirus infection, and has wide application prospect.
XL888 according to the invention is a small molecule compound which still does not show any cytotoxicity at 5. Mu.M in Vero cells. Thus, CC 50 (half lethal concentration) greater than 5. Mu.M. XL888 was able to dose-dependently inhibit viral replication for both adenoviruses (AdV 3 and AdV 5). IC of AdV3 in Vero cells 50 (median inhibitory concentration) of only 0.17. Mu.M, IC for AdV5 50 It was 0.48. Mu.M. By calculation, the Selection Index (SI) of XL888 was greater than 10 on both adenoviruses, indicating that XL888 has a broad spectrum of anti-adenoviruses
The invention provides a novel anti-adenovirus medicament-XL 888, which overcomes the technical defect that the prior art does not have an anti-virus medicament for adenovirus infection.
The XL888 serving as a novel antitumor drug in research and development is already in a phase I clinical test, and has a large amount of clinical safety experimental data. If the indications are expanded to the medicines for treating the adenovirus infection, the risk of failure of clinical safety tests can be obviously reduced, and the time and the cost for developing new drugs are greatly saved.
As inventive supplementary proof of the claims of the present invention, also present several important aspects:
the expected income and commercial value after the technical scheme of the invention is converted are as follows: the invention focuses on the field of core treatment by meeting clinical requirements as a guide, and has huge commercial value and expected income after conversion based on clinical value, medicinal economic value and commercial value of products. The technical scheme of the invention fills the technical blank in the industry at home and abroad: the invention provides a new technology of antiviral drugs for adenovirus infection.
Drawings
FIG. 1 shows the 5% CO content at 37 ℃ of Vero cells according to an example of the invention with XL888 at various concentration gradients 2 Cell viability profile of Vero cells relative to non-drug treated cells measured after 48 hours incubation in the incubator of (a);
FIG. 2 is a graph showing the percent inhibition of Vero cells to AdV3 after incubation at 37 ℃ for 48 hours after adding XL888 with different concentration gradients to Vero cells provided in the example of the present invention, infecting AdV3 with MOI 0.55, and treating the Vero cells with different drug concentration gradients relative to non-drug-added cells after viral infection;
FIG. 3 is a graph showing the percent inhibition of Vero cells to AdV5 after adding XL888 with different concentration gradients to Vero cells provided in the example of the present invention, infecting AdV5 with MOI 1.1, and after incubating at 37 ℃ for 48 hours, the Vero cells treated with different drug concentration gradients are compared with non-drug-added cells after viral infection.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to the following embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
1. Illustrative embodiments are explained. This section is an illustrative example developed to explain the claims in order to enable those skilled in the art to fully understand how to implement the present invention.
The application of XL888 provided by the embodiment of the invention in preparation of medicines and adenovirus inhibitors for relieving and/or preventing and/or treating adenovirus infection.
The chemical structural formula of XL888 provided by the embodiment of the invention is as follows:
the adenovirus provided by the embodiment of the invention can be any one or more of human adenovirus types 1, 3, 4, 5, 7, 11, 14, 40, 41 and 55.
The agents provided by the embodiments of the present invention for alleviating and/or preventing and/or treating adenoviral infections act by inhibiting the activity of adenovirus replication.
The medicament for relieving and/or preventing and/or treating adenovirus infection provided by the embodiment of the invention comprises XL888 and a pharmaceutically acceptable carrier.
The dosage form of the medicament for relieving and/or preventing and/or treating the adenovirus infection provided by the embodiment of the invention is any clinically acceptable oral administration dosage form, injection administration dosage form or external administration dosage form.
The medicine for relieving and/or preventing and/or treating adenovirus infection provided by the embodiment of the invention is tablets, capsules, granules, oral liquid and injection.
2. Application examples. In order to prove the creativity and the technical value of the technical scheme of the invention, the part is the application example of the technical scheme of the claims on specific products or related technologies.
XL888 provided in the embodiment of the invention is applied to preparation of medicaments and adenovirus inhibitors for relieving and/or preventing and/or treating adenovirus infection. XL888 can effectively inhibit replication of adenovirus in a nontoxic range, can be further developed into a medicament for treating diseases caused by adenovirus infection, and has wide application prospect. In view of the fact that no drug for the treatment of adenovirus infection is currently approved on the market, the present invention provides a new technology for the treatment of adenovirus infection.
3. Evidence of the relevant effects of the examples. The embodiment of the invention has some positive effects in the process of research and development or use, and indeed has great advantages compared with the prior art, and the following contents are described by combining data, charts and the like in the test process.
The invention detects the toxicity of XL888 to cells on a Vero cell line of African green monkey, and simultaneously determines the inhibition effect of XL888 to two types of adenovirus, namely adenovirus type 3 (AdV 3) and adenovirus type 5 (AdV 5) in the Vero cell line. The results show that the small molecule compound XL888 has remarkable dose-dependent anti-adenovirus activity on both AdV3 and AdV5. Therefore, the XL888 is a novel antiviral drug aiming at adenovirus, has the advantages of good safety, high selection index, broad-spectrum adenovirus resistance and the like, can be used for developing drugs for treating adenovirus infection, and has wide application prospect.
1. Experimental materials:
(1) Cell line, animal and virus for experiment
Vero cells were purchased from American Type Culture Collection (ATCC);
the strains used were: adenovirus type B AdV3, adenovirus type C AdV5.
The drugs required for the experiment: XL888 was purchased from Selleck Chemicals; in cell experiments, drugs were dissolved in DMSO.
Reagents required for the experiment:
DMEM medium, fetal Bovine Serum (FBS) were purchased from GIBCO;
the CellTiter-Glo cell proliferation assay kit was purchased from Promega corporation.
(2) Instrument for experiment
EnSpire multifunctional microplate reader from Perkinelmer;
CO 2 cell culture chambers were purchased from Thermo;
the Operetta CLS high content imaging analysis system was purchased from Perkinelmer.
2. Experimental methods
2.1XL888 cytotoxicity assays were as follows:
(1) Vero of African green monkey kidney cell line at 2X 10 4 Each well was plated in a 96-well plate and incubated for 24h.
(2) Adding XL888 diluted with culture medium to different gradient concentrations, and 5% CO at 37 deg.C 2 The cultivation was continued for 48h.
(3) The cell viability after different concentrations of drug treatment was tested to detect the cytotoxicity of XL 888.
(4) The median Cytotoxic Concentration (CC) of the drug was calculated by plotting Graphpad against Cell relative Cell viability (Cell viability) versus log drug concentration 50 )。
2.2 evaluation of the antiviral activity of XL888 on adenovirus AdV3 in cell models includes:
(1) Vero of African green monkey kidney cell line at 2X 10 4 Each well was plated in a 96-well plate and cultured for 24 hours. To test their antiviral efficacy, vero cells were infected with adenovirus AdV3 at 0.55MOI (multiplicity of infection).
(2) Adding XL888 diluted with culture medium to different gradient concentrations at 37 deg.C, 5% 2 The cultivation was continued for 48h.
(3) The number of positive cells infected with virus (the number of Hexon positive cells) in the wells of the drug-treated and untreated groups was tested by Indirect immunofluorescence assay (IFA) to assess the level of replication of adenovirus AdV3 after treatment with different concentrations of XL 888.
(4) The median Inhibitory Concentration (IC) of drug to adenovirus AdV3 was calculated by plotting Graphpad as the Inhibition rate (Inhibition rate) against the logarithm of the drug concentration 50 ). The selection index for adenovirus AdV3 on Vero cell line was calculated for XL 888.
2.3 evaluation of the antiviral activity of XL888 on adenovirus AdV5 in a cell model as follows:
1) Vero of African green monkey kidney cell line at 2X 10 4 Each well was plated in a 96-well plate and cultured for 24 hours. To test their antiviral effect, vero cells were infected with adenovirus AdV5 at 1.1MOI (multiplicity of infection).
2) Simultaneously adding XL888 diluted with culture medium to different gradient concentrations, containing 5% CO at 37% 2 The cultivation was continued for 48h.
3) The number of virus-infected positive cells (Hexon positive cells) in the wells of the drug-treated and untreated groups was examined using an Indirect immunofluorescence assay (IFA) to assess the level of replication of adenovirus AdV5 following treatment with different concentrations of XL 888.
4) The median Inhibitory Concentration (IC) of drug to adenovirus AdV5 was calculated by plotting Graphpad as the Inhibition rate (Inhibition rate) against the logarithm of the drug concentration 50 ). The selection index for adenovirus AdV5 on Vero cell line was calculated for XL 888.
2.4 evaluation of cytotoxicity of XL888 in Vero cell line
(1) Cell culture
After 2 passages, the frozen and recovered cells are subjected to amplification culture by using a DMEM medium containing 10% fetal calf serum and double antibiotics (penicillin 100U/ml and streptomycin 100 mu g/ml), and the inoculation density is not lower than 1x10 4 cell/ml, passage density not higher than 5X10 4 cell/ml。
(2) Drug-treated cells
Vero cells were grown at 1X10 4 Cells/well (volume 100 μ L) were seeded in 96-well cell culture plates and cultured for 24h until the confluency of the wells reached 80%; the drug was prepared in 200. Mu.L of medium (DMEM medium +2% serum + double antibody) per well and added to the corresponding well and mixed well. The drug was set up in 6 concentration gradients, each gradient concentration being 2 multiple wells with final concentrations of 0.02. Mu.M, 0.06. Mu.M, 0.19. Mu.M, 0.56. Mu.M, 1.67. Mu.M and 5. Mu.M, containing 5% CO at 37% 2 The cultivation was continued for 48h.
(3) Calculating the toxicity of the drug to the cells in each detection hole
The supernatant was removed and 100. Mu.L of CellTiter-
Reagents, plates were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The chemiluminescence readings were detected with an ensspire microplate reader and the cell viability was calculated.
Cell viability (%) = drug treated group/untreated control group 100%
The results are shown in FIG. 1, and the cell viability of Vero cells treated with XL888 at the maximum concentration of 5 μ M for 48h is slightly different from that of the control group, which indicates that XL888 has weak toxicity to cells at the concentration, and the half toxicity concentration CC of the XL888 is 50 Greater than 5. Mu.M.
2.5 evaluation of XL888 Activity against AdV3 adenovirus in Vero cell line
(1) Cell culture
After 2 passages, the frozen and recovered cells are subjected to amplification culture by using a DMEM medium containing 10% fetal calf serum and double antibiotics (penicillin 100U/ml and streptomycin 100 mu g/ml), and the inoculation density is not lower than 1x10 4 cell/ml, passage density not higher than 5x10 4 cell/ml。
(2) Drug-treated cells
Vero cells were grown at 1X10 4 Cells/well (volume 100 μ L) were seeded in 96-well cell culture plates and cultured for 24h until the confluency of the wells reached 80%; adV3 virus at 0.55MOI (multiplicity of infection) was added to the infected group, and drugs at each gradient concentration (5. Mu.M as the starting concentration, 6 gradients were serially diluted in 3-fold gradient, two wells per gradient) were added to a total volume of 200. Mu.L of culture medium (DMEM medium +2% serum + double antibody) and cultured in a cell culture chamber at 37 ℃ for 48 hours.
(3) Detection of specific fluorescently-labeled viruses by indirect immunofluorescence
The cell culture plates were washed twice with the cells in PBS solution and fixed with 4% paraformaldehyde (4% pfa in PBS) for 20 minutes at room temperature. The fixed samples were washed 3 times with PBST (0.05% tween 20 in PBS), and then incubated for 1 hour at room temperature in blocking buffer (3% BSA,0.3% Triton X-100 and 10% FBS in PBS). Then incubated overnight at 4 ℃ in binding buffer (3% BSA,0.3% Triton X-100 in PBS) for mouse monoclonal antibody against adenovirus hexon protein (dilution 1. After 3 rinses with PBST, the samples were incubated in a binding buffer of goat FITC-conjugated anti-mouse secondary antibody (dilution 1 1000) and DAPI (dilution 1 10000) for 1 hour at room temperature in the dark. Rinsing with PBST 3 times, and using
CLS TM The high content analysis system observes the sample and then takes and analyzes the image.
(4) Calculating the inhibition rate of the drug in each detection hole to the virus
Cells were labeled by DAPI staining, and the intensity of FITC staining represents the level of viral replication. FITC background fluorescence was measured in uninfected control cells. Cells with FITC intensity three times higher than the control cells were defined as adenovirus infection positive cells. The ratio of adenovirus infection positive cells in total cells was calculated.
Inhibition (%) =100% - (drug-treated well-blank)/(virus control well-blank) × 100%
The results are shown in FIG. 2, XL888 significantly inhibits replication of adenovirus AdV3 in a dose-dependent manner with half the effective concentration IC 50 The concentration was 0.17. Mu.M.
(5) Drug selection index calculation
The drug Selection Index (SI) is used for judging the safety range of the drug effect, the selection index is more than 3 to be effective, and the larger the index is, the larger the safety range is. The calculation formula is as follows: SI = CC 50 /IC 50
According to the data, XL888 has a selection index of more than 10 on Vero for adenovirus AdV3, and has effective anti-adenovirus AdV3 activity.
2.6 evaluation of XL888 anti-AdV 5 AdV Activity in Vero cell lines
(1) Cell culture
After 2 passages, the frozen and recovered cells are subjected to amplification culture by using a DMEM medium containing 10% fetal calf serum and double antibiotics (penicillin 100U/ml and streptomycin 100 mu g/ml), and the inoculation density is not lower than 1x10 4 cell/ml, passage density not higher than 5x10 4 cell/ml。
(2) Drug-treated cells
Vero cells were grown at 1X10 4 Cells/well (volume 100 μ L) were seeded in 96-well cell culture plates and cultured for 24h until the confluency of the wells reached 80%; the infection group was cultured at 37 ℃ for 48 hours in a cell culture incubator with addition of 1.1MOI (multiplicity of infection) of AdV5 virus and simultaneous addition of each of the drugs at each concentration gradient (starting at 5. Mu.M, serially diluted at 3-fold gradient for 6 gradients, two multiple wells per gradient) to a total volume of 200. Mu.L of culture medium (DMEM medium +2% serum + double antibody).
(3) Indirect immunofluorescence method for detecting specific fluorescence labeled virus
The cell culture plates were washed twice with the cells in PBS solution and fixed with 4% paraformaldehyde (4% pfa in PBS) for 20 minutes at room temperature. The immobilized samples were washed 3 times with PBST (0.05% tween 20 in PBS), then incubated for 1 hour at room temperature in blocking buffer (3% BSA,0.3% Triton X-100 and 10% FBS in PBS). The mouse monoclonal antibody was then raised against the adenovirus hexon protein(dilution 1. After 3 rinses with PBST, the samples were incubated in a binding buffer of goat FITC-conjugated anti-mouse secondary antibody (dilution 1 1000) and DAPI (dilution 1 10000) for 1 hour at room temperature in the dark. Rinsing with PBST 3 times, and using
CLS TM The high content analysis system observes the sample and then takes and analyzes the image.
(4) Calculating the inhibition rate of the drug in each detection hole to the virus
Cells were labeled by DAPI staining, and the intensity of FITC staining represents the level of viral replication. FITC background fluorescence was measured in uninfected control cells. Cells with FITC intensity three times higher than the control cells were defined as adenovirus infection positive cells. The ratio of adenovirus infection positive cells in total cells was calculated.
Inhibition (%) =100% - (drug-treated well-blank)/(virus control well-blank) × 100%
The results are shown in FIG. 3, XL888 significantly inhibits replication of adenovirus AdV5 in a dose-dependent manner with half the effective concentration IC 50 The concentration was 0.48. Mu.M.
(5) Drug selection index calculation
The drug Selection Index (SI) is used for judging the safety range of the drug effect, the selection index is more than 3 to be effective, and the larger the index is, the larger the safety range is. The calculation formula is as follows: SI = CC 50 /IC 50
In combination with the data, XL888 has a selection index of greater than 10 on Vero for adenovirus AdV5, and has effective anti-adenovirus AdV5 activity.
The above description is only for the purpose of illustrating the embodiments of the present invention, and the scope of the present invention should not be limited thereto, and any modifications, equivalents and improvements made by those skilled in the art within the technical scope of the present invention as disclosed in the present invention should be covered by the scope of the present invention.
Claims (7)
1. Use of XL888 for the preparation of a medicament for the alleviation and/or prevention and/or treatment of adenoviral infections;
the medicament for relieving and/or preventing and/or treating the adenovirus infection comprises XL888 and a pharmaceutically acceptable carrier.
2. The use according to claim 1, wherein the adenovirus is one or more of adenovirus type 1, 3, 4, 5, 7, 11, 14, 40, 41 and 55.
3. The use according to claim 1, wherein the adenovirus comprises a group B adenovirus AdV3 subtype, a group C adenovirus AdV5 subtype.
4. The use according to claim 1, wherein the adenovirus infection is one or more of a respiratory disease, an intestinal disease, and a corneal disease.
5. The use according to claim 1, wherein the medicament for alleviating and/or preventing and/or treating adenovirus infection is in any one of clinically acceptable oral administration dosage forms or injection administration dosage forms.
6. The use according to claim 1, wherein the medicament for alleviating and/or preventing and/or treating adenovirus infection is in any clinically acceptable form for external administration.
7. The use according to claim 1, wherein the medicament for alleviating and/or preventing and/or treating adenovirus infection is a tablet, a capsule, a granule, an oral liquid, an injection.
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| Heat Shock Protein 90 Chaperones E1A Early Protein of Adenovirus 5 and Is Essential for Replication of the Virus;Iga Dalidowska等;《International Journal of Molecular Sciences》;20210218;第22卷(第4期);第8-10页"3. 讨论"项下 * |
| Hsp90抑制剂的研究进展;张钟元等;《中国医药生物技术》;20210228;第16卷(第1期);第44页左栏第1-6行 * |
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