CN104069106A - Application of benzamide compound in preparation of medicine for activating latent human immunodeficiency virus - Google Patents
Application of benzamide compound in preparation of medicine for activating latent human immunodeficiency virus Download PDFInfo
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- CN104069106A CN104069106A CN201410117771.9A CN201410117771A CN104069106A CN 104069106 A CN104069106 A CN 104069106A CN 201410117771 A CN201410117771 A CN 201410117771A CN 104069106 A CN104069106 A CN 104069106A
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Abstract
The invention discloses an Aapplication of a benzamide compound in preparation of a medicine for activating latent human immunodeficiency viruses, and an application of a composition of the benzamide compound and one or more anti-human immunodeficiency virus medicines in preparation of a medicine for inhibiting and/or eliminating latent human immunodeficiency viruses. Due to adoption of the medicine, the latent human immunodeficiency viruses can be efficiently and continuously activating latent human immunodeficiency viruses for a long time, and thus acquired immune deficiency syndrome treatment is possible.
Description
Technical field
The present invention relates to field of medicaments, be specifically related to benzamide compound and activate the application of hiding in HIV (human immunodeficiency virus) medicine in preparation.
Background technology
Acquired immune deficiency syndrome (AIDS) (AIDS) is by HIV (human immunodeficiency virus) (HIV), to be infected the infectious disease of the serious harm human health causing, be one of the most serious public disease of facing of the current mankind, its effective prevention and thoroughly healing are still global difficult problems.On the 19th the World AIDS Conference of holding on July 22nd, 2012 (http://aids2012.org), international AIDS brainstrust is unanimously thought and be there is some evidence " mankind prevent and treat AIDS Epidemic and welcome Important Change point " " acquired immune deficiency syndrome (AIDS) changes a kind of chronic disease into gradually from ' century incurable disease ' ".This is because the existing approximately 30 kinds of retrovirus medicines in the whole world can form effective Therapeutic Method, if drug combination, i.e. " highly active antiretroviral therapy (HAART) ", HIV (human immunodeficiency virus) in patient body can be controlled to extremely low level, greatly delay PD, improve patient's life-span and quality of life.Yet existing medicine is treatment of AIDS thoroughly all, the infected needs lifelong medication, once drug withdrawal, the HIV (human immunodeficiency virus) amount in body will rebound fast.Therefore, current the World AIDS Conference is classified the following mankind as by " treatment of AIDS " and is prevented and treated one of most important target of acquired immune deficiency syndrome (AIDS).
Existence just because of latent infection and the bunker of hiding of HIV (human immunodeficiency virus), just causes existing AIDS-treating medicine cannot eradicate HIV (human immunodeficiency virus), thoroughly treatment of AIDS.The latent infection of so-called HIV (human immunodeficiency virus), is incorporated into its viral gene in people's genome after referring to AIDS viral infection host cell, keep the latency that do not copy, so the medicine that those antiviral copy does not have inhibitory action to it.Once but condition maturity (after drug withdrawal), these viruses of hiding can be recovered replication capacity again, discharge the virion making new advances and infect contiguous immunocyte.The bunker of hiding of HIV (human immunodeficiency virus) has the persistency of height, comprises that highly active antiretroviral therapy (HARRT claims again " HAART ") is all helpless to the bunker of hiding of removing HIV (human immunodeficiency virus) in interior chemotherapy when its tranquillization.
At present, generally believe that removing the HIV (human immunodeficiency virus) bunker of hiding is one of key of thorough treatment of AIDS.Research finds that histon deacetylase (HDAC) (HDAC) inhibitor, Protein kinase C (PKC) antagonist, dnmt rna (DNMT) inhibitor etc. all have certain activation to the HIV (human immunodeficiency virus) of hiding.In the recent period, on the top Scientific Periodicals < < Nature > > magazine of the world, reported a up-to-date breakthrough achievement: a kind of cancer therapy drug Vorinostat--Vorinostat(HDAC inhibitor) can activate the HIV (human immunodeficiency virus) of hiding in human body.In its experiment, research worker takes medicine Vorinostat to eight patients infected hivs, and these eight the infecteds are before at antiretroviral therapy, and stable disease.After having taken Vorinostat, the virus load in patient body has on average increased by 4.5 times, and this has implied that the HIV (human immunodeficiency virus) of hiding in their body after taking medicine is activated.This part of report proved that hdac inhibitor can excite the HIV (human immunodeficiency virus) of hiding in bunker effectively first in transforming clinical research, is key one step of thorough treatment of AIDS.In combining under use of such medicine and anti-reverse transcription medicine, treatment of AIDS becomes possibility.
Chidamide (CS055/HBI-8000); selectivity Antibiotic FR 901228 (HDACi); chemistry N-(2-amino-4-fluorophenyl)-4-[N-[(E by name)-3-(3-pyridine) acryloyl group] aminomethyl] Benzoylamide (N-(2-Amino-4-fluorophenyl)-4-[N-[(E)-3-(3-pyridyl) acryloyl] aminomethyl] benzamide, C
22h
19fN
4o
2, molecular weight390.41), be a kind of novel Antibiotic FR 901228, it has anti-tumor activity and can strengthen the cytotoxicity for the immunocyte mediation of tumor cell.But up to now, at home and abroad there is no chidamide at the application of the medicine of hiding as activation HIV (human immunodeficiency virus), i.e. the research report of the functional healing of acquired immune deficiency syndrome (AIDS) aspect.
The major reason that acquired immune deficiency syndrome (AIDS) is difficult to be cured is completely can hide form the storehouse of hiding in tranquillization memory CD4+ cell due to HIV (human immunodeficiency virus).To remove the HIV (human immunodeficiency virus) in patient body completely, need to remove on the one hand the inside and outside virion with infection ability of infection cell, also will remove on the other hand those and continue to hide and be hidden in the provirus gene of hiding in bunker in infection cell neutralization.Now, just concentrating in the world advantage strength at the strategy of research and development " shock and kill " (first stimulate latent virus to bring back to life with HIV (human immunodeficiency virus) activator, then treat with Anti-AIDS Drugs), to be used as the scheme for the treatment of of AIDS.
Related art scheme is as follows: 1. every hole is by 0.5ml10%FBS(volume fraction) 1640 spread 24 orifice plates containing 80000 J-lat10.6 cells.2. chidamide, and control drug SAHA, TSA, Apcidin is respectively with the ultimate density incubated cell shown in scheming, and making every hole cumulative volume is 1ml.3. 24h, 48h, 72h, 96h, 120h after drug treating, distinguish collecting cell in 1.5ml EP pipe, and 1000 turn, 3 minutes.Remove supernatant, with PBS, clean 2 times, 1000 turn, 3 minutes.Then use the PBS re-suspended cell of 0.2ml, prepare re-suspended cell liquid.4. utilize the expression of the reporter gene green fluorescent protein of Flow cytometry re-suspended cell suspension.Analyze the activation efficiency of HIV (human immunodeficiency virus) latent infection cell, thereby obtain pharmaceutically-active dose-effect relationship.
Result shows (Fig. 1～4), and along with the rising of chidamide drug level, the cell number of expressing green fluorescence in cell model increases; Under 1 μ M concentration, its activation effect of chidamide effect 96h reaches the highest (71%), and does not have obviously and weaken (69%) at 120 hours; Do not add the HIV (human immunodeficiency virus) latent infection cell that chidamide and control drug are processed, the cell proportion of its fluorescence positive is less than 10%.Results suggest of the present invention, chidamide compound has significant activation to the cell of HIV (human immunodeficiency virus) latent infection, and has dose-effect relationship.
Related art scheme is as follows: 1. every hole press 0.1ml10%FBS 1640 containing 1*10
4individual ACH-2 cell spreads 96 orifice plates.2. chidamide, and control drug SAHA, TSA, Apcidin is respectively with the ultimate density incubated cell shown in scheming, and making every hole cumulative volume is 0.2ml.3. 24h, 48h, 72h, 96h, 120h after drug treating, collect respectively supernatant, centrifugal removal cell, the Triton-100 that then working concentration is 5%.Utilize ELISA method (Lu, L., Pan, C., Li, Y., Lu, H., Wu, H., Jiang, S. (2012) .A bivalent recombinant protein inactivates HIV-1by targeting the gp41prehairpin fusion intermediate induced by CD4D1D2domains.Retrovirology.2012,9:104doi:10.1186/1742-4690-9-104.) measure the content that variable concentrations is processed ACH-2 cell conditioned medium p24, analyze the activation efficiency of HIV (human immunodeficiency virus) latent infection cell.
Result shows (Fig. 5～8), and chidamide compound also has significant activation to the HIV (human immunodeficiency virus) of hiding in this live virus model, and has dose-effect relationship.
Related art scheme is as follows: 1. every hole press 0.1ml10%FBS 1640 containing 1*10
4individual J1.1 cell spreads 96 orifice plates.2. chidamide, and control drug SAHA, TSA, Apcidin is respectively with the ultimate density incubated cell shown in scheming, and making every hole cumulative volume is 0.2ml.3. 24h, 48h, 72h, 96h, 120h after drug treating, collect respectively supernatant, centrifugal removal cell, the Triton-100 that then working concentration is 5%.Utilize ELISA method (Lu, L., Pan, C., Li, Y., Lu, H., Wu, H., Jiang, S. (2012) .A bivalent recombinant protein inactivates HIV-1by targeting the gp41prehairpin fusion intermediate induced by CD4D1D2domains.Retrovirology.2012,9:104doi:10.1186/1742-4690-9-104.) measure the content that variable concentrations is processed J1.1 cell conditioned medium p24, analyze the activation efficiency of HIV (human immunodeficiency virus) latent infection cell.
Result shows (Fig. 9～12), and chidamide compound also has significant activation to the HIV (human immunodeficiency virus) of hiding in this live virus model, and has dose-effect relationship.
Summary of the invention
Technical problem solved by the invention is to provide a kind of benzamide compound to activate the application of hiding in HIV (human immunodeficiency virus) medicine in preparation.In the present invention, utilize the multiple internationally recognized HIV (human immunodeficiency virus) model of hiding, provide benzamide compound (especially chidamide) to there is the hide activity of HIV (human immunodeficiency virus) of Activation In Vitro.
The invention provides a kind of benzamide compound and activate the application of hiding in HIV (human immunodeficiency virus) medicine in preparation; Described benzamide compound is as follows:
Wherein, R
1, R
2, R
3and R
4be hydrogen, C independently of one another
1～4straight or branched alkyl, halogen, hydroxyl or amino; R
5, R
6and R
7be hydrogen, C independently of one another
1～4straight or branched alkyl, halogen, hydroxyl or amino.
In the present invention, the preferred chidamide of described benzamide compound (CS055/HBI-8000).Described chidamide (CS055/HBI-8000) can be referring to concrete document: Cancer Chemother Pharmacol (2012) 69:901 – 909DOI10.1007/s00280-011-1766-x; Biochem.J. (2012) 443,735 – 746 (Printed in Great Britain) doi:10.1042/BJ20111685; Cancer Chemother Pharmacol DOI10.1007/s00280-012-1847-5.
In the present invention, described benzamide compound, especially chidamide can be induced and be activated the HIV (human immunodeficiency virus) of hiding, and can be in conjunction with the Anti-AIDS Drugs of clinical use, or under people's immune system effect, accelerate the hide removing in storehouse of HIV (human immunodeficiency virus), finally reach the effect of thorough treatment of AIDS.
In the present invention, described benzamide compound also can form HIV (human immunodeficiency virus) latent infection with methylated transferase inhibitor, cytokine or the agent of NF-κ B signal activation and activate compositions, activates the medicine of the HIV (human immunodeficiency virus) of hiding for preparation.
Described methylated transferase inhibitor can be U-18496.
Described cytokine can be interleukin-17 or TNF-α.
Described NF-κ B signal activation agent can be tyrosine kinase inhibitor (preferably 12-deoxidation phorbol-13-acetic acid (prostratin) or 12-deoxidation phorbol-13-monoester (12-hydroxyphorbol-13-monoester)).Described 12-deoxidation phorbol-13-acetic acid (Prostratin) thus can activate NF-κ B by protein kinase C pathway and activate the HIV (human immunodeficiency virus) hide in tranquillization memory CD4T+ cell.
The present invention also provides described benzamide compound (preferably chidamide) preparing inhibition and/or eliminating the application in HIV (human immunodeficiency virus) latent virus medicine with the compositions of one or more Anti-AIDS Drugs.
The medicine of described AIDS virus resisting can be the medicine of the AIDS virus resisting of this area routine, is preferably: efabirenz (NRTI), non-nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor, entry inhibitor or integrase inhibitor etc.
Described efabirenz is preferably: zidovudine (Zidovudine, AZT), didanosine (Didanosin, ddl, Videx), zalcitabine (Zalcitabine, ddc), stavudine (Stavudine, d4T), lamivudine (Lamivudine, 3TC) or Abacavir (abacavir, 1592U89Ziagen).
Described non-nucleoside reverse transcriptase inhibitor (NNRTI) is preferably: nevirapine (Nevirapin), Delavirdine (Delavird) or efavirenz (Efavirene).
Described protease inhibitor is preferably: Saquinavir (Saguinavir), indinavir (Indinavir) or amprenavir (Amprenavir).
Described entry inhibitor is preferably: T-20 (Enfuvirtide).
Described integrase inhibitor is preferably: Merck (raltegravir).
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: the invention provides benzamide compound and activate the application of hiding in HIV (human immunodeficiency virus) medicine in preparation, its effect is efficient and the persistent period is long, and can further form HIV (human immunodeficiency virus) latent infection activation compositions with methylated transferase inhibitor, cytokine or the agent of NF-κ B signal activation, after being combined with existing Anti-AIDS Drugs, make treatment of AIDS become possibility.
Accompanying drawing explanation
Fig. 1 be concentration be 1 μ M chidamide different time to J-lat10.6 cell in the activation effect of latent infection HIV (human immunodeficiency virus) gene.
Fig. 2 be concentration be 0.5 μ M chidamide different time to J-lat10.6 cell in the activation effect of latent infection HIV (human immunodeficiency virus) gene.
Fig. 3 be concentration be 0.25 μ M chidamide different time to J-lat10.6 cell in the activation effect of latent infection HIV (human immunodeficiency virus) gene.
Fig. 4 be concentration be 0.125 μ M chidamide different time to J-lat10.6 cell in the activation effect of latent infection HIV (human immunodeficiency virus) gene.
Fig. 5 be concentration be 1.25 μ M chidamides different time to ACH2 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Fig. 6 be concentration be 0.625 μ M chidamide different time to ACH2 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Fig. 7 be concentration be 0.3125 μ M chidamide different time to ACH2 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Fig. 8 be concentration be 0.156 μ M chidamide different time to ACH2 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Fig. 9 be concentration be 1.25 μ M chidamides different time to J1.1 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Figure 10 be concentration be 0.625 μ M chidamide different time to J1.1 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Figure 11 be concentration be 0.3125 μ M chidamide different time to J1.1 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Figure 12 be concentration be 0.156 μ M chidamide different time to J1.1 cell in the activation effect of latent infection HIV (human immunodeficiency virus).
Figure 13 is that chidamide is combined the experimental result of use with hiv inhibitor.
The specific embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to conventional method and condition, or selects according to catalogue.
Embodiment 1: on J-lat full length clone10.6 (being called for short J-lat10.6) cell model, chidamide activates the detection of the HIV (human immunodeficiency virus) activity of hiding
In the present embodiment, selected HIV (human immunodeficiency virus) latent infection cell model is J-lat10.6 strain (the Jordan A that takes from American National health academy AIDS reference reagent planning department (NIH AIDS Research and Reference Reagent Program), Bisgrove D, Verdin E.HIV reproducibly establishes a latent infection after acute infection of T cells in vitro.EMBO J22:1868-1877,2003).J-lat10.6 strain cell is the A6 clone strain of setting up after the HIV (human immunodeficiency virus) pseudovirus infection human T-cell by Carrying Green Fluorescent Protein gene, is in the world general HIV (human immunodeficiency virus) latent infection cell membrane.The biological property of this cell model is to be integrated with HIV (human immunodeficiency virus) pseudogene, but viral gene is not expressed (gene silencing).Green fluorescent protein can observe and utilize Flow cytometry owing to having on living cells, and therefore, green fluorescent protein is as the reporter gene of this model, the labelling whether being activated as latent infection cell.
The present invention's chidamide purity used is greater than 99%, is dissolved in DMSO(purchased from SIGMA), storage liquid concentration is 10mM.Control drug Vorinostat(is hereinafter to be referred as SAHA, Sigma company), Trichostatin A(is hereinafter to be referred as TSA, Sigma company), Apcidin is all purchased from Sigma company.Many experimentatioies show that SAHA, TSA, Apcidin all have the activity of good activating dormant infection HIV (human immunodeficiency virus), in this patent as positive control medicine.
Embodiment 2: at the upper chidamide of ACH-2 latent infection cell model (HIV (human immunodeficiency virus) of living model), activate the detection of the HIV (human immunodeficiency virus) activity of hiding
In the present embodiment, selected HIV (human immunodeficiency virus) latent infection cell model is ACH-2 cell strain (the Folks TM that takes from American National health academy AIDS reference reagent planning department (NIH AIDS Research and Reference Reagent Program), Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, Fauci AS.Tumor necrosis factor a induces expression of human immunodeficiency virus in a chronically infected T-cell clone.Proc Natl Acad Sci USA86:2365-2368, 1989.).This cell derived, in cem cell, obtains from a Caucasia girl separation with it of suffering from acute lymphoblastic leukemia for 4 years old at first.In each ACH-2 cell, infect and have a provirus HIV (human immunodeficiency virus), it can reach p24 by low scale, can induce great expression AIDS viral infection virion with TNF-α.This system is the HIV (human immunodeficiency virus) of living hide model, better the HIV (human immunodeficiency virus) latent cells in analogue body.Medicine source used is as implemented described in one.
Embodiment 3: at the upper chidamide of J1.1 latent infection cell model (HIV (human immunodeficiency virus) of living model), activate the detection of the HIV (human immunodeficiency virus) activity of hiding
In the present embodiment, selected HIV (human immunodeficiency virus) latent infection cell model is J1.1 cell strain (the Perez VL that takes from American National health academy AIDS reference reagent planning department (NIH AIDS Research and Reference Reagent Program), Rowe T, Justement JS, Butera ST, June CH, Folks TM.An HIV-1-infected T cell clone defective in IL-2production and Ca2+mobilization after CD3stimulation.J Immunol147:3145-3148,1991.).Come from Jurkat cell, be from the Jurkat cell separation of AIDS viral infection to the cell strain with latent infection HIV (human immunodeficiency virus).This system is also the HIV (human immunodeficiency virus) of living hide model, better the HIV (human immunodeficiency virus) latent cells in analogue body.Medicine source used is as implemented described in 1.
Embodiment 4: chidamide is combined use experiment with hiv inhibitor
Utilizing HIV latent cells is that target cell TZM-bI conventional in ACH2 and HIV infection model has detected chidamide and combines the effect of use with hiv inhibitor.Result is illustrated in fig. 13 shown below, and this medicine can effectively activate HIV latent cells, produces the HIV-1 virus of living, and this virus has infectivity, can infect the target cell that contains CD4 and CCR5 receptor.But when hiv inhibitor exists, the viral infection that is activated is significantly suppressed.
Experimental technique: 1, the 100 μ L1640 culture fluid (GIBCO) that contain 10000 ACH-2 cells are planted in 96 orifice plates; 2, add again 50 μ L chidamide (CS055) and anti HIV-1 virus medicines, nevirapine for example, indinavir (ultimate density is the IC90 of 4 times), then add 50 μ L1640 culture medium (GIBCO); 3,37 ℃, 5%CO
2condition under, in incubator, cultivate 3 days; 4, at the 3rd day that cultivates, supernatant is removed, in every hole, added 8000 TZM-bI cells; 6, add after TZM-bI 48 hours, detect the fluorescein value (the results are shown in Figure 13) of TZM-bI cell.
In Figure 13, (1) cell group is ACH2+TZM-bI, does not add any medicine, the fluorescent value of background when can be observed latent cells and target cell and coexisting.(vertical coordinate fluorescent value RLU, represents the degree that HIV-1 virus infects and copies target cell, the higher expression viral infection of value with to copy degree higher)
(2) CS0550.5 μ M group is that the CS055 of 0.5 μ M acts on HIV latent cells ACH2, and under the effect of medicine, the HIV genome of hiding in ACH2 cell is activated, and produces the HIV-1 virus of living.These live viruses that are activated have infectivity.Infect after TZM-bI cell, can detect HIV virus replication fluorescent value (for the 3-4 of background fluorescence value doubly, there is significant difference)
(3) CS0551 μ M group is that the CS055 of 1 μ M acts on HIV latent cells ACH2, and under the effect of medicine, the HIV genome of hiding in ACH2 cell is activated, and produces the HIV-1 virus of living.These live viruses that are activated have infectivity.Infect after TZM-bI cell, can detect virus replication fluorescent value (for the 5-6 of background fluorescence value doubly, there is significant difference)
(4) TSA100nM and SAHA1 μ M organize positive medicine matched group, are respectively 100nM TSA and 1 μ M SAHA effect HIV latent cells ACH2, and under the effect of medicine, the HIV genome of hiding in ACH2 cell is activated, and produce the HIV-1 virus of living.These live viruses that are activated have infectivity.Infect after TZM-bI cell, the fluorescent value of virus replication can be detected.
(5) CS055+NVP group is that the CS055 of 1 μ M adds hiv inhibitor NVP(NNRTI class inhibitor when acting on HIV latent cells ACH2, name is called a kind of apple Wei Laping Nevirapine, final concentration is 4 times of IC90), consistent with the operation of CS0551 μ M group afterwards, observe the HIV-1 virus of hiding that is activated to the infection of TZM-bI cell suppressed (it represents that fluorescent value that HIV copies is significantly lower than CS0551 μ M group).
(6) CS055+IDV group is that the CS055 of 1 μ M adds hiv inhibitor IDV(PI class inhibitor when acting on HIV latent cells ACH2, name is called indinavir indinavir, final concentration is 4 times of IC90), consistent with the operation of CS0551 μ M group afterwards, observe the HIV-1 virus of hiding that is activated to the infection of TZM-bI cell suppressed (it represents that fluorescent value that HIV copies is significantly lower than CS0551 μ M group).
Claims (7)
1. a benzamide compound activates the application of hiding in HIV (human immunodeficiency virus) medicine in preparation; Described benzamide compound is as follows:
Wherein, R
1, R
2, R
3and R
4be hydrogen, C independently of one another
1～4straight or branched alkyl, halogen, hydroxyl or amino; R
5, R
6and R
7be hydrogen, C independently of one another
1～4straight or branched alkyl, halogen, hydroxyl or amino.
2. application as claimed in claim 1, is characterized in that: the HIV (human immunodeficiency virus) latent infection that described benzamide compound and methylated transferase inhibitor, cytokine or the agent of NF-κ B signal activation form activates compositions and activates the application of hiding in HIV (human immunodeficiency virus) medicine in preparation.
3. application as claimed in claim 1 or 2, is characterized in that: described benzamide compound is chidamide.
4. application as claimed in claim 2, is characterized in that: described methylated transferase inhibitor is U-18496; Described cytokine is interleukin-17 or TNF-α; Described NF-κ B signal activation agent is tyrosine kinase inhibitor; Described tyrosine kinase inhibitor is 12-deoxidation phorbol-13-acetic acid or 12-deoxidation phorbol-13-monoester.
5. the compositions of benzamide compound as claimed in claim 1 and one or more Anti-AIDS Drugs is being prepared inhibition and/or is being eliminated the application of hiding in HIV (human immunodeficiency virus) medicine.
6. application as claimed in claim 5, is characterized in that: the medicine of described AIDS virus resisting is: efabirenz, non-nucleoside reverse transcriptase inhibitor, protease inhibitor, entry inhibitor or integrase inhibitor.
7. application as claimed in claim 6, is characterized in that: described efabirenz is: zidovudine, didanosine, zalcitabine, stavudine, lamivudine or Abacavir;
Described non-nucleoside reverse transcriptase inhibitor is: nevirapine, Delavirdine or efavirenz;
Described protease inhibitor is: Saquinavir, indinavir or amprenavir;
Described entry inhibitor is: T-20;
Described integrase inhibitor is: Merck.
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| US11535670B2 (en) | 2016-05-11 | 2022-12-27 | Huyabio International, Llc | Combination therapies of HDAC inhibitors and PD-L1 inhibitors |
| US12122833B2 (en) | 2019-08-14 | 2024-10-22 | Huyabio International, Llc | Combination therapies of HDAC inhibitors and PD-1 inhibitors |
| WO2023004994A1 (en) * | 2021-07-28 | 2023-02-02 | 中国医科大学附属第一医院 | Marker in hiv and/or siv-infected cell and application of marker |
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