CN-120983440-B - Use of raltitrexed in the manufacture of a medicament for the treatment of diseases caused by adenovirus infection

CN120983440BCN 120983440 BCN120983440 BCN 120983440BCN-120983440-B

Abstract

The present invention provides the use of raltitrexed in the treatment of diseases caused by adenovirus infection, including but not limited to respiratory tract infection, gastrointestinal tract infection and keratitis caused by adenovirus. When the activity of the raltitrexed against adenovirus is tested at the cellular level, the viral infectivity is tested on a human non-small cell lung cancer cell line (A549 cells) model by adopting the viral infectivity dose of 100TCID50, the result shows that the raltitrexed has remarkable inhibitory effect on the adenovirus, EC 50 ＝8.98nM,CC 50 is more than 187.5nM, the raltitrexed is found to have remarkable inhibitory effect after entering cells, and the effect of the raltitrexed on remarkably inhibiting the replication of the virus is also observed on a hDSG mouse model. Accordingly, raltitrexed is useful in the treatment of diseases caused by adenovirus infection.

Inventors

TONG YIGANG
ZHANG LIHONG
XU SHAN
MA YINGLUN

Assignees

北京化工大学

Dates

Publication Date: 20260508
Application Date: 20250715
Priority Date: 20240718

Claims (8)

1. Use of raltitrexed in the manufacture of a medicament for the treatment of a disease caused by an adenovirus infection.
2. The use according to claim 1, wherein the disease caused by adenovirus infection comprises a light, medium or severe infection caused by adenovirus.
3. The use according to claim 1, wherein the diseases caused by adenovirus infection are respiratory tract infections, gastrointestinal tract infections and keratitis.
4. The use according to claim 1, wherein the adenoviruses are of 113 types, belonging to the subgenera a-G7.
5. The use according to claim 1, wherein the adenovirus belongs to the subgenera B, C, E, of the type HAdV-1 to 7, 14, 21 and 55.
6. The use according to claim 1, wherein the adenovirus is HAdV-B3, HAdVB, or HAdV-B55.
7. The use according to any one of claims 1 to 6, wherein the medicament is a pharmaceutical composition comprising raltitrexed and pharmaceutically acceptable excipients.
8. Use of raltitrexed in the manufacture of a pharmaceutical composition for the treatment of a disease caused by an adenovirus infection.

Description

Use of raltitrexed in the manufacture of a medicament for the treatment of diseases caused by adenovirus infection The application claims priority from the prior application, which is filed by 2024, month 07 and 18 to China national intellectual property agency, with patent application number 2024109680748, and the application is named as the use of Raltitrexed in preparing medicines for treating diseases caused by adenovirus infection. This prior application is incorporated by reference in its entirety into this application. Technical Field The invention belongs to the technical field of medicines, and particularly relates to application of raltitrexed in treating adenovirus infection. In particular, it relates to the use of raltitrexed and pharmaceutical compositions containing raltitrexed in medicaments for the treatment of diseases caused by adenovirus infections, including but not limited to respiratory tract infections, gastrointestinal tract infections and keratitis caused by adenovirus. Background Human adenovirus (Human Adenovirus, HAdV) belongs to the genus Adenoviridae, mammalian adenovirus, is a non-enveloped, double-stranded DNA virus, and has a genome of about 33-36 kb in length. HAdV is an important pathogen that causes respiratory tract infections and is widely distributed in nature. In addition to infecting the respiratory tract, HAdV has a wide range of tissue tropism and can infect a number of sites of the digestive tract, cornea, genitourinary tract, cardiac muscle, nervous system, etc. To date, HAdV new types frequently appear, and 113 types have been identified at present, belonging to the subgenera A-G7. Among them, HAdV causing respiratory tract infection mainly belongs to the subgenera B, C, E, and the most common types are HAdV-1 to 7, 14, 21 and 55. In China, HAdV-B3 and HAdV-B7 are the main types prevalent in children, and HAdV-B55 is an important causative agent of acquired pneumonia in the adult community. Studies have shown that HAdV-B55 is produced by homologous recombination of different types of HAdV, has a strong proliferation capacity, and has a high occurrence rate of severe symptoms in infected patients. In recent years, respiratory tract infection caused by adenovirus is in a high-rise state in China, and outbreak epidemic situation is extremely easy to cause. The health of the common people is affected, and the local communities are popular for many times, so that public health and safety are seriously threatened. Pneumonia caused by adenovirus infection can be up to 50% mortality in immunodeficient patients if not treated in time. Even in non-immunodeficiency patients, the detection rate of adenovirus increases. No specific medicine is used for treating adenovirus infection at home and abroad. Currently, adenovirus vaccines exist in the united states mainly for types 4 and 7, but do not have broad spectrum. In view of the severity of adenovirus infection and the current lack of effective treatment means, the development of effective medicaments for adenovirus infection has important practical significance and urgency. Raltitrexed (ZD-1694) is a quinolinyl folic acid analogue with a mechanism that exerts its antitumor effect by specifically inhibiting Thymidylate Synthase (TS). The drug is actively absorbed into cells through a reduced folic acid/methotrexate cell membrane carrier and rapidly and widely metabolized into polyglutamic acid form in the cells via folic acid polyglutamic acid synthetase. These multimeric forms of raltitrexed are more potent TS inhibitors than the original drug and their inhibitory effect is more durable due to their prolonged retention in the cell. In preclinical studies, raltitrexed has been shown to have significantly stronger inhibitory effects on human colon tumor cell lines than the traditional antitumor drug fluorouracil. Disclosure of Invention Although the inhibitory effect of raltitrexed on human colon tumor cell lines has been widely reported, its activity on adenoviruses has not been reported. The invention tests the activity of the raltitrexed in inhibiting adenovirus on an in vitro cell model, and the result shows that the half effective concentration EC 50 reaches 8.98nM, and the raltitrexed has good inhibition effect. The technical scheme of the invention is as follows: use of raltitrexed in the manufacture of a medicament for the treatment of a disease caused by an adenovirus infection. Diseases caused by adenovirus infection in the present invention include minor, intermediate, and severe infections caused by adenovirus, including, but not limited to, respiratory tract infections, gastrointestinal tract infections, and keratitis, for example. According to the invention, the adenovirus has 113 types and belongs to the subgenera A-G7. According to the invention, the adenovirus belongs to the subgenera B, C, E, and is of the type HAdV-1-7, 14, 21 and 55. According to the invention, the adenovirus is HAdV-B3, HAdV-B7 or HAdV-B