KR20200077480A - A pharmaceutical composition for preventing or treating a human cytomegalovirus disease comprising a gamma secretase inhibitor, and a method for screening a therapeutic agent for a human cytomegalovirus disease using gamma secretase - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating human cytomegalovirus infection disease including a gamma secretase inhibitor, and a method for screening an agent for treating human cytomegalovirus infection disease using gamma secretase. Various inhibitors against gamma secretase developed as an agent for treating Alzheimer′s disease or as an anticancer agent are shown to inhibit proliferation of human cytomegalovirus, and thus suggest feasibility of development of a novel agent for treating human cytomegalovirus infection disease. Therefore, the gamma secretase inhibitor is expected to be used as an antiviral medicine against human cytomegalovirus causing a brain development disorder, various types of cancers, and even death of a person with weakened immune systems.

Description

A pharmaceutical composition for preventing or treating human cytomegalovirus-infectious disease, including a gamma secretase inhibitor, and a screening method for treating a human cytomegalovirus-infectious disease treatment using gamma secretase {A pharmaceutical composition for preventing or treating a human cytomegalovirus disease comprising a gamma secretase inhibitor, and a method for screening a therapeutic agent for a human cytomegalovirus disease using gamma secretase}

The present invention includes a gamma secretase (Gamma secretase) inhibitor as an active ingredient, human cytomegalovirus (HCMV) pharmaceutical composition for preventing or treating infectious diseases, and human cytomegalovirus using gamma secretase It relates to a screening method of a therapeutic agent for an infectious disease.

Unlike the herpes simplex virus, human cytomegalovirus (HCMV), known as the Herpes virus-5, has strong species specificity for cultured cells and proliferates only in human fetal fibroblasts. Human cytomegalovirus infection worldwide is one of the most common congenital infections in about 1% of newborns, and 40% of the population is infected with human cytomegalovirus. The symptoms of congenital CMV (Cytomegalovirus) infection are about 10~15%, and 50~90% of them have complications such as mental retardation or sensorineural hearing loss.

According to the Korea Centers for Disease Control and Prevention, the incidence of disease due to infection is very high in Europe and the United States, and in Korea, more than 95% of adults remain asymptomatic, and the incidence of disease is not as high as in Europe and the United States. It is done. However, it is known that in the case of leukemia, cancer, immunodeficiency, and a person who is administered an immunosuppressive agent after organ transplantation, the latent state is reactivated to cause diseases such as retinitis, infection, and colitis. In particular, the number of patients with domestic organ transplants is increasing every year, so the importance of HCMV treatment is increasing.

Human cytomegalovirus has no symptoms when infected with healthy people, but can cause serious symptoms when infected with infants or immunodeficiency patients with relatively weak immunity. In particular, it is known as a cause of further cancer malignancies such as brain tumor, colorectal cancer, and breast cancer.

Human cytomegalovirus affects parts of the liver, brain, lungs, ears and eyes, and human cytomegalovirus infection diseases include pneumonia, cytomegalovirus mononucleosis, cytomegalovirus retinitis, cytomegalovirus hepatitis, thousand giant cells Viral infections, cytomegalovirus antigenemia, etc. To date, as treatments for human cytomegalovirus-infectious diseases, anti-human cytomegalovirus drugs, antiviral drugs, and immunoglobulin have been mainly used, but these treatments have been used to treat blood, kidney function, and liver function during treatment. There are problems such as hassle to be monitored, and most target human cytomegalovirus-infected diseases other than cancer.

On the other hand, gamma secretase (Gamma secretase) is a protease that has a variety of cell membrane proteins as a substrate as an enzyme complex present in the cell membrane. While this enzyme was found to play a critical role in producing amyloid beta, a protein that causes Alzheimer's dementia, research has been conducted on various inhibitors of gamma secretase as a way of treating Alzheimer's dementia (Korea Publication No. KR10) -2006-0003107), a study to treat a variety of human cytomegalovirus-related diseases by using gamma secretase inhibitors used for the treatment of Alzheimer's dementia or anticancer purposes for the purpose of replication of human cytomegalovirus and inhibition of progeny virus production Is still incomplete.

Accordingly, the present inventors provide a gamma secretase (Gamma secretase) inhibitor by using a human cytomegalovirus (HCMV) pharmaceutical composition for preventing or treating infectious diseases, by providing a gamma secretase inhibitor It is to provide a composition for suppressing a cell virus or a method for screening a therapeutic agent for a human cytomegalovirus infection disease.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the object of the present invention as described above, the present invention comprises a gamma secretase (gamma secretase) inhibitor as an active ingredient, human cytomegalovirus (human cytomegalovirus, HCMV) pharmaceutical composition for preventing or treating infectious diseases Gives

In addition, the present invention provides a composition for inhibiting human cytomegalovirus (HCMV), comprising a gamma secretase inhibitor as an active ingredient.

In addition, the present invention comprises the steps of: (a) treating the candidate substance to gamma secretase; (b) measuring the activity of the gamma secretase treated with the candidate substance; (c) measuring the activity of the gamma secretase that is not treated with the candidate substance; And (d) selecting a candidate substance having a reduced activity measured in step (b) than the activity measured in step (c), a screening method for treating a therapeutic agent for human cytomegalovirus (HCMV) infection. Gives

In one embodiment of the invention, the gamma secretase inhibitor is N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[ N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT), (5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy -(2R)-benzylhexaonyl)-L-leucine-L-phenylalanineamide((5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu- L-phe-amide, L-685,458), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5 -Phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide ((S,S)-2-[2-(3,5-difluorophenyl) -acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide, compound E) It may be characterized by being selected from the group.

In another embodiment of the present invention, the human cytomegalovirus infection disease is brain tumor, colorectal cancer, breast cancer, pharyngitis, premature birth, cerebellum, mental retardation, congenital brain malformation, immunodeficiency, liver damage, jaundice, hypertrophy (Enlarged spleen ), seizures and pneumonia may be characterized by being selected from the group consisting of.

In another embodiment of the present invention, the activity measurement of the gamma secretase is performed by any one selected from the group consisting of enzyme immunoassay (ELISA), immunoprecipitation, and Western Blotting. It may be a feature.

As a new therapeutic agent for human cytomegalovirus (HCMV) infection, it has been shown that inhibitors for various gamma secretase enzymes developed for the treatment of Alzheimer's or anticancer drugs inhibit the proliferation of human cytomegalovirus (HCMV). It was confirmed that there is a possibility of development. Therefore, the pharmaceutical composition for preventing or treating human cytomegalovirus (HCMV) infection disease according to the present invention can inhibit the proliferation of human cytomegalovirus (HCMV) by inhibiting gamma secretase enzyme function, It is expected to be used as an antiviral drug against human giant cell virus (HCMV), which causes brain development disorders, various types of cancer, and even death of people with weakened immunity.

1A is a representative gamma secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[N It is a diagram schematically showing a method for confirming the inhibitory effect of progeny virus formation in human giant cell virus (HCMV) by -(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) .
Figures 1b and 1c, when treated with gamma secretase inhibitor DAPT, compared to the control group DMSO treated group (upper line in Fig. 1b) DAPT treated group (lower line in Fig. It is a figure showing the results of the investigation by performing immunofluorescence staining using an antibody against the HCMV-derived protein IE1/2 (Immunofluorescence) and a graph accordingly.
Figure 2a is a progeny virus of human cytomegalovirus by diluting 1/10 by serial dilution with 10 μM at 100 pM in order to investigate the pharmacological properties of DAPT-induced cytomegalovirus inhibitory effect. It is a diagram showing the result of comparing the formation efficiency.
FIG. 2B is a diagram showing the relative progeny production graph of progeny virus formation efficiency of human cytomegalovirus by diluting DAPT by 1/10 in serial dilution by 10 pM at 100 pM.
Figure 3a is a gamma secretase inhibitor DAPT, as well as other representative gamma secretase inhibitors (5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)- Benzylhexaonyl)-L-Leucyl-L-phenylalanineamide((5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu-L-phe-amide , L-685,458), or (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2, 3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide ((S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N -(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide, compound E) It is a diagram showing the results of confirming that progeny virus formation is inhibited.
Figure 3b is a relative progeny production (relative progeny production) that the progeny virus formation of human giant cell virus is inhibited by DAPT as well as other representative gamma secretase inhibitors L-685,458, compound E compared to the control DMSO treated group It is a graph.

The present invention can be applied to various transformations and can have various embodiments, and specific embodiments will be illustrated in the drawings and described in detail in the detailed description. However, this is not intended to limit the present invention to specific embodiments, and should be understood to include all conversions, equivalents, and substitutes included in the spirit and scope of the present invention. In the description of the present invention, when it is determined that a detailed description of related known technologies may obscure the subject matter of the present invention, the detailed description will be omitted.

Human cytomegalovirus (HCMV) is known to infect 50-90% of the world's population. The infection of the virus does not show any symptoms in healthy adults, but it is a very fatal condition in patients with reduced immunity, such as patients with organ transplants or AIDS. In addition, infections in the fetal period may also cause severe developmental disorders of the central nervous system, and recent studies have shown that it induces various types of cancer.

As a result, the present inventors confirmed that an inhibitor against gamma secretase originally developed for the treatment of Alzheimer's or anticancer drugs inhibits the proliferation of human cytomegalovirus, as a new therapeutic agent for human cytomegalovirus infection. The present invention was completed by confirming the possibility of development.

In one embodiment of the present invention, when the human giant cell virus is infected with human-derived HFFs (Human foreskin fibroblasts) cells, when the gamma secretase inhibitor DAPT is treated, progeny virus formation is reduced compared to the control group DMSO treated group As a result of investigation by performing immunofluorescence staining (Immunofluorescence), it was confirmed that the progeny virus (number of infected HFFs) was lower in the experimental group treated with DAPT than the control group (see Example 2).

In another embodiment of the present invention, it was confirmed that the inhibition of progeny virus formation in human cytomegalovirus by DAPT, a representative gamma secretase inhibitor, is concentration dependent (see Example 3).

In another embodiment of the present invention, the HCMV progeny virus is formed using another gamma secretase inhibitor L-685,458 and compound E (CPDE) in order to exclude the possibility that the above confirmed results are DAPT-only side-effects. As a result of investigating the inhibitory effect, L-685,458 and compound E also confirmed the same effect as DAPT, indicating that the inhibitory effect on the formation of progeny virus in human cytomegalovirus is regulated by the inhibition of gamma secretase activity rather than the unique function of DAPT. It was confirmed (see Example 4).

Accordingly, the present invention can provide a pharmaceutical composition for preventing or treating diseases of human cytomegalovirus (HCMV) infection, which includes a gamma secretase inhibitor as an active ingredient.

The gamma secretase inhibitor is N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[N-(3,5-Difluorophenacetyl) )- L -alanyl]-S-phenylglycine t-butyl ester, DAPT), (5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexaonyl )-L-Leucyl-L-phenylalanineamide ((5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu-L-phe-amide, L- 685,458), and (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-di Hydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide((S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1 -methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide, compound E). It may be, but is not limited thereto.

The N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[N-(3,5-Difluorophenacetyl)-L-alanyl] -S-phenylglycine t-butyl ester, DAPT) is a white solid, molecular formula C ₂₃ H ₂₆ F ₂ N ₂ O ₄ , molecular weight 432.46, CAS No. 208255-80-5.

(5S)-(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanyl)-L-leucine-L-phenylalanineamide ((5S)-(tert -butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu-L-phe-amide, L-685,458) has the molecular formula C ₃₉ H ₅₂ N ₄ O ₆ , molecular weight 672.85, CAS No. 292632-98-5.

Said (S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H -Benzo[e][1,4]diazepin-3-yl)-propionamide ((S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl- 2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)-propionamide, compound E) is an off-white powder, molecular formula C ₂₇ H ₂₄ F ₂ N ₄ O ₃ , molecular weight 490.5.

In addition, the human cytomegalovirus infection diseases include brain tumor, colorectal cancer, breast cancer, pharyngitis, premature birth, cerebellum, mental retardation, congenital brain malformation, immunodeficiency, liver damage, jaundice, enlarged spleen, seizures and pneumonia. It may be characterized by being selected from the group consisting, but is not limited thereto.

As used in the present invention, the term "prevention" refers to all actions that inhibit or delay the onset of human giant cell virus infection by proactively administering the pharmaceutical composition according to the present invention prior to human giant cell virus infection. .

As used in the present invention, the term "treatment" refers to all actions in which the symptoms of a human cytomegalovirus-infecting disease are improved or beneficially altered by administration of the pharmaceutical composition according to the present invention after infection with a human macrocytovirus.

Thus, suitable carriers, excipients, and diluents commonly used to prepare pharmaceutical compositions may be further included. In addition, it can be formulated and used in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, and sterile injection solutions according to a conventional method.

Carriers, excipients, and diluents that may be included in the composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl Cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxy benzoate, propylhydroxy benzoate, talc, magnesium stearate, and mineral oil. When formulating the composition, it is usually prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, and the like.

The pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "a pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of patient's disease, severity, and activity of the drug , Sensitivity to the drug, time of administration, route of administration and rate of excretion, duration of treatment, factors including co-drugs used, and other factors well known in the medical field.

The pharmaceutical composition according to the present invention, in order to enhance the therapeutic effect, preferably can be administered concurrently (simultaneous), separately (separate), or sequentially (sequential) with the drug used in combination, it can be administered single or multiple . Considering all of the above factors, it is important to administer an amount that can achieve the maximum effect in a minimal amount without side effects, which can be easily determined by those skilled in the art. Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, condition, weight, absorption of active ingredients in the body, inactivation rate and excretion rate, disease type, and drugs used in combination.

The pharmaceutical composition of the present invention can be administered to a subject by various routes. All modes of administration can be expected, for example, oral administration, intranasal administration, bronchoscopy, arterial injection, intravenous injection, subcutaneous injection, intramuscular injection, or intraperitoneal injection. Daily dosage is preferably divided into once to several times a day, but is not limited thereto.

The pharmaceutical composition of the present invention is determined according to the type of drug as the active ingredient, along with various related factors such as the disease to be treated, the route of administration, the patient's age, sex, weight, and the severity of the disease.

In addition, as another aspect of the present invention, a method for screening a therapeutic agent for human cytomegalovirus infection disease by measuring the activity of gamma secretase in cells infected with human cytomegalovirus (HCMV) .

Therefore, the present invention comprises the steps of treating a candidate substance with gamma secretase; Measuring the activity of the gamma secretase treated with the candidate substance; Measuring the activity of the gamma secretase without treating the candidate substance; And (c) provides a method for screening of a therapeutic agent for human cytomegalovirus infection disease, comprising the step of selecting a candidate substance having a reduced activity measured in step (b) than the activity measured in step (c).

The candidate substance of the present invention means an unknown substance used in screening to measure the activity of gamma secretase, and is preferably selected from the group consisting of compounds, microbial cultures or extracts, natural product extracts, nucleic acids, and peptides The nucleic acid may be selected from the group consisting of microRNA, siRNA, shRNA, antisense RNA, aptamer, locked nucleic acid (LNA), peptide nucleic acid (PNA), and morpholino. It may be, but is not limited to this.

The term “microRNA” used in the present invention means a short non-coding RNA composed of about 22 base sequences. It is known that it functions as a post-transcriptional regulator in the gene expression process. Target mRNAs with complementary base sequences are complementarily bound to inhibit degradation of target mRNAs or translation into proteins.

As used in the present invention, the term “siRNA (small interfering RNA)” refers to short double-chain RNA capable of inducing RNA interference (RNAi) phenomenon through cleavage of a specific mRNA. It consists of a sense RNA strand with a sequence homologous to the mRNA of the target gene and an antisense RNA strand with a sequence complementary thereto. Since siRNA can suppress the expression of a target gene, it is provided as an efficient gene knock-down method or as a method of gene therapy.

In the present invention, the term “small hairpin RNA” (shRNA) means a nucleotide composed of 50-60 strands on a single strand, and forms a stem-loop structure in vivo. That is, shRNA is an RNA sequence that creates a tight hairpin structure for suppressing gene expression through RNA interference. The long RNAs of 15-30 nucleotides complementarily to either side of the loop region of 5-10 nucleotides base-pair to form a double-stranded stem. shRNA is transduced into cells through a vector containing a U6 promoter to always be expressed, and is usually delivered to daughter cells so that gene expression suppression is inherited. The shRNA hairpin structure is cut by an intracellular mechanism to become an siRNA and then binds to an RNA-induced silencing complex (RISC). These RISCs bind and cleave the mRNA. shRNA is transcribed by RNA polymerase.

The step of measuring the activity of gamma secretase of the cells of the present invention can be carried out through various methods known in the art that can measure the amount of protein produced by the expression of gamma secretase. Preferably, the expression level of the protein can be measured by Western blotting, Enzyme-Linked ImmunoSorbent Assay (ELISA), or immunoprecipitation, and is very simple and easy by those skilled in the art. It can be carried out, but is not limited to this.

Hereinafter, preferred embodiments are provided to help understanding of the present invention. However, the following examples are only provided to more easily understand the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1. Experiment preparation and method

1-1. Cell culture

Human foreskin fibroblast (HFF) cells were used with a passage number of 16-20. HFF cells were cultured at 37° C., 5% CO _{2 in} a medium with 10% fetal bovine serum (FBS) added to DMEM (Dulbecco's Modified Eagle's Medium).

1-2. Virus infection

After the human giant cell virus was infected with the host cell HFF cells with a multiplicity of infection (MOI) of 0.01, the medium was changed at intervals of 3 days until the whole cell became a human giant cell virus infection. After that, it was confirmed that HCMV was infected with all the cells, and the supernatant was harvested to obtain a human giant cell virus. The titration of the obtained human cytomegalovirus was performed by confirming IE1/2 by ICC (Immunocytochemistry), and after infecting the human cytomegalovirus, HFF cells were divided and grown to about 90%, and then infection was performed.

1-3. Western blot

HFF cells were lysed with RIPA buffer containing PMSF, a protease inhibitor. After loading the same amount of protein sample onto the SDS-PAGE gel, it was transferred to a PVDF membrane. The transferred gel was blocked by adding 5% skim milk to TBST (150 mM NaCl, 10 mM Tris/HCl, 0.1% (v/v) Tween 20, pH 8.0). Subsequently, protein expression was confirmed using an antibody against the target protein.

1-4. Immunocytochemistry (ICC)

HFF cells were fixed using 4% PFA and then permeablized with 100% ethanol. Then, the expression of IE 1/2 was confirmed as an antibody against the target protein.

Example 2. Confirmation of reduction in progeny virus production of human giant cell virus by DAPT treatment

Human cytomegalovirus (HCMV) is treated in a dish in which HFFs (Human foreskin fibroblasts) are cultured at a concentration of 0.1 multiplicity of infection (MOI). Progeny viruses produced by replication from infected HFFs are obtained by harvesting a culture medium of cells and infected with newly cultured HFFs. In the step of virus replication and progeny virus production, control DMSO or a representative gamma secretase inhibitor, N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine After treatment with t-butyl ester (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, DAPT), progeny virus was collected and infected with newly cultured HFFs and infected. The cells were observed by an immunofluorescence method using an antibody against HCMV-derived protein IE1/2. As a result, in the experimental group treated with DAPT, progeny virus production (number of infected HFFs) was significantly lower than that of the control group (FIG. 1 ).

Example 3. Concentration dependence of gamma secretase inhibitor

N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[N-(3,5-Difluorophenacetyl)- L -alanyl]- To investigate the pharmacological properties of human cytomegalovirus (HCMV) suppression of progeny virus formation by S-phenylglycine t-butyl ester (DAPT), dilute 1/10 by serial dilution and treat from 100pM to 10μM As a result of comparing the efficiency of progeny virus formation, the degree of inhibition of human cytomegalovirus replication and progeny virus production showed a concentration-dependent tendency of gamma secretase inhibitors (FIG. 2 ).

Example 4. Confirmation of the inhibitory effect of progeny virus formation in human cytomegalovirus by inhibition of gamma secretase activity

N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (N-[N-(3,5-Difluorophenacetyl)- L -alanyl]- Another representative inhibitor of gamma secretase (5S) to exclude the possibility that the inhibitory effect of progeny virus formation by treatment with S-phenylglycine t-butyl ester (DAPT) is a side-effect of the inhibitor. -(tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexaonyl)-L-leucine-L-phenylalanineamide((5S)-(tert-butoxycarbonylamino)- 6-phenyl-(4R)-hydroxy-(2R)-benzylhexanoyl)-L-leu-L-phe-amide, L-685,458), and (S,S)-2-[2-(3,5-di Fluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1 H-benzo[e][1,4]diazepin-3-yl)- Propionamide ((S,S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[ e][1,4]diazepin-3-yl)-propionamide, compound E) was treated to confirm that the formation of progeny virus was also inhibited when the same experiment was carried out. It was supported through inhibition of gamma secretase activity (FIG. 3).

Since the specific parts of the present invention have been described in detail above, for those skilled in the art, it is obvious that this specific technique is only a preferred embodiment, whereby the scope of the present invention is not limited. something to do. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (2)

A pharmaceutical composition for the prevention or treatment of human cytomegalovirus (HCMV) infection, comprising a gamma secretase inhibitor as an active ingredient,
The gamma secretase inhibitor is DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester), L-685,458 ((5S)- (tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexaonyl)-L-leucine-L-phenylalanineamide), and compound E((S,S)- 2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1 ,4]diazepin-3-yl)-propionamide),
The human cytomegalovirus infection disease is characterized by being selected from the group consisting of pharyngitis, premature birth, cerebellum, mental retardation, congenital brain malformation, liver damage, jaundice, enlarged spleen, seizures and pneumonia. Pharmaceutical composition for the prevention or treatment of cell virus infection disease.
Selected from the group consisting of pharyngitis, premature birth, cerebellum, mental retardation, congenital brain malformation, liver damage, jaundice, enlarged spleen, seizures and pneumonia, which contain gamma secretase inhibitors as active ingredients. As a composition for inhibiting human cytomegalovirus (HCMV) infection disease, human cytomegalovirus proliferation,
The gamma secretase inhibitor is DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester), L-685,458 ((5S)- (tert-butoxycarbonylamino)-6-phenyl-(4R)-hydroxy-(2R)-benzylhexaonyl)-L-leucine-L-phenylalanineamide), and compound E((S,S)- 2-[2-(3,5-difluorophenyl)-acetylamino]-N-(1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1 ,4] diazepin-3-yl)-propionamide), characterized in that it is selected from the group consisting of human giant cell virus proliferation inhibitory composition.

Images