CN116672346B - Application of pramipexole in preparation of medicines for treating diseases caused by VZV - Google Patents
Application of pramipexole in preparation of medicines for treating diseases caused by VZV Download PDFInfo
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- CN116672346B CN116672346B CN202310679787.8A CN202310679787A CN116672346B CN 116672346 B CN116672346 B CN 116672346B CN 202310679787 A CN202310679787 A CN 202310679787A CN 116672346 B CN116672346 B CN 116672346B
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- FASDKYOPVNHBLU-ZETCQYMHSA-N pramipexole Chemical compound C1[C@@H](NCCC)CCC2=C1SC(N)=N2 FASDKYOPVNHBLU-ZETCQYMHSA-N 0.000 title claims abstract description 14
- 229960003089 pramipexole Drugs 0.000 title claims abstract description 14
- 201000010099 disease Diseases 0.000 title claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title claims description 6
- 229940079593 drug Drugs 0.000 title description 10
- 208000007514 Herpes zoster Diseases 0.000 claims abstract description 6
- 241000701085 Human alphaherpesvirus 3 Species 0.000 claims description 41
- 230000010076 replication Effects 0.000 claims description 6
- 206010010741 Conjunctivitis Diseases 0.000 claims description 2
- 239000002671 adjuvant Substances 0.000 claims description 2
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- 206010014599 encephalitis Diseases 0.000 claims description 2
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- OGSBUKJUDHAQEA-WMCAAGNKSA-N pralatrexate Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CC(CC#C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OGSBUKJUDHAQEA-WMCAAGNKSA-N 0.000 description 4
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- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 1
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- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
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- 238000012258 culturing Methods 0.000 description 1
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- 229940012356 eye drops Drugs 0.000 description 1
- 210000000744 eyelid Anatomy 0.000 description 1
- 229960004396 famciclovir Drugs 0.000 description 1
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 description 1
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- ODZBBRURCPAEIQ-PIXDULNESA-N helpin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(\C=C\Br)=C1 ODZBBRURCPAEIQ-PIXDULNESA-N 0.000 description 1
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
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- 239000007928 intraperitoneal injection Substances 0.000 description 1
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- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
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- 239000002245 particle Substances 0.000 description 1
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- 229960001412 pentobarbital Drugs 0.000 description 1
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229960000214 pralatrexate Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000010814 radioimmunoprecipitation assay Methods 0.000 description 1
- 230000007420 reactivation Effects 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Virology (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides an application of pramipexole in preparing a medicament for treating a disease caused by VZV, and a corresponding method and a pharmaceutical composition; the study of the invention proves that the antiviral activity and the safety of the pramipexole with extremely low dosage to Varicella Zoster (VZV) are superior to those of the traditional antiviral drug acyclovir.
Description
Technical Field
The invention belongs to the technical field of antiviral drugs, and particularly provides application of pramipexole in preparation of a drug for treating diseases caused by VZV, a corresponding method and a corresponding pharmaceutical composition.
Background
Varicella Zoster Virus (VZV) is a DNA virus that generally latent infects the trigeminal ganglion and nervous system and when host immune function is impaired, reactivation causes shingles. Shingles is manifested by the appearance of herpes and associated localized neuropathic pain in areas of the skin corresponding to unilateral sensory nerves of the body. At present, acyclovir (ACV) is mainly used for antiviral treatment in clinic, including oral administration and local emulsion coating. However, with the application of the medicines, the ACV has limited effect of treating the VZV infection, and the antiviral medicines aiming at the VZV treatment are single in variety, only acyclovir, famciclovir, brivudine, foscarnet and the like exist at present, and the medicines are basically derivatives and nucleoside analogues of the medicines, and no research report about the inhibition of the VZV by the pralatrexed at home and abroad exists at present, and no application and report on the preparation of the medicines for preventing and/or treating the diseases infected by the VZV by the pralatrexed exist at present.
Disclosure of Invention
In one aspect, the invention provides the use of pramipexole in the manufacture of a medicament for the treatment of a disease caused by VZV.
Further, pralatrexed inhibits replication of VZV.
Further, the VZV-induced disease is varicella, herpes zoster, encephalitis, conjunctivitis.
In another aspect, the invention provides a medicament for treating a disease caused by VZV, the medicament comprising pramipexole.
Further, the pralatrexed in the medicine is the only effective component.
Further, the medicament is an oral or injectable, preferably an injectable.
Further, the medicine is an external preparation, preferably eye drops, ointment, cream, lotion, gel.
Further, the medicament comprises pharmaceutically acceptable auxiliary materials.
In another aspect, the invention provides a method of non-therapeutically inhibiting VZV proliferation or inhibiting VZV infection comprising the step of administering pralatrexed or a medicament comprising pralatrexed.
The term pramipexole in the present invention may be used interchangeably with Folotyn, pralatrexate/PDX to refer to the same meaning, namely, a compound having a CAS number of 146464-95-1.
The non-therapeutic methods described herein include, but are not limited to, methods for scientific research and methods for inhibiting non-pathogenic invisible infection.
Other drugs for the treatment of HSV infections, including but not limited to acyclovir, are not excluded from the drugs of the present application other than pramipexole.
The skilled person can select the appropriate dosage form known or under study for the pramipexole according to the needs of the specific disease and the technical conditions in the pharmaceutical field, and these dosage forms are not limited to the above dosage forms. The dosage form may be conventionally prepared from known or studied adjuvants including, but not limited to, solvents, co-solvents, stabilizers, pH modifiers, coating agents, fillers, antioxidants, preservatives, etc.
In the invention, the antiviral activity and the safety of the pramipexole sand (PDX) to Varicella Zoster (VZV) are superior to those of the traditional antiviral drug Acyclovir (ACV) at extremely low dosage. PDX significantly inhibited VZV replication, IC in ARPE-19 cells 50 ＝2.942nM，CC 50 27.913. Mu.M, SI > 10000, and ACV versus VZV IC 50 2.694 mu M, CC 50 > 100. Mu.M, SI > 37. Thus, PDX is excellent in antiviral activity against VZV and is highly safe at therapeutic doses and suitable for use as an antiviral agent.
Drawings
FIG. 1 shows the effect of PDX on inhibiting VZV replication.
FIG. 2 is a comparison of the in vitro anti-VZV infection effects of PDX and ACV.
FIG. 3A is a schematic representation of VZV in vivo infection modeling.
FIG. 3B shows the ORF61 mRNA expression of the murine cornea tissue in experiments where PDX inhibited VZV infection on the cornea.
Fig. 3C shows the change in body weight of mice in experiments in which PDX inhibited VZV infection on the cornea.
Fig. 3D shows corneal damage in experimental mice in experiments with inhibition of VZV infection by PDX on the cornea.
Fig. 3E is the integrity and thickness of the cornea of a laboratory mouse in experiments where PDX inhibited VZV infection on the cornea.
FIG. 4 shows the effect of Folotyn on inhibiting the proliferation of cytomegalovirus.
Detailed Description
The present invention is described in detail below with reference to specific examples. The following examples are given for illustration only, and the scope of the invention is defined by the claims and is not limited to the following examples.
EXAMPLE 1PDX concentration-dependent inhibition of VZV replication
Exponentially growing ARPE-19 cells were seeded into 12-well cell culture plates so that each well contained 2X 10 5 Individual cells were cultured in 1ml of DMEM medium with 10% FBS. The culture conditions are constant temperature and humidity at 37 ℃ and 5 percent CO 2 . After 24 hours, VZV (oka strain) virus particles stored at-80 ℃ were thawed on ice and ARPE-19 cells were infected at a titer of moi=1. After 2 hours, the PDX stock was diluted with DMSO to a concentration of 0, 10, 50, 100, 500, 1000nM in the cell culture medium, and to ensure that the DMSO content was less than 1%. After culturing for 48 hours, the fluorescence intensity of GFP was observed by a fluorescence microscope, and it was found that the fluorescence intensity of VZV-GFP gradually decreased with PDX treatment. RNA and protein were harvested by lysing cells using TRizol and RIPA. The mRNA expression and gE protein expression of ORF-61 of VZV were examined by qPCR and Western-blot. As shown in fig. 1, PDX treatment was found to significantly inhibit VZV replication.
In addition, the applicant tried the effect of PDX on inhibition of Human Cytomegalovirus (HCMV) of the herpesviridae family: as shown in FIG. 4, HFF (human foreskin fibroblasts were infected with cytomegalovirus, 1. Mu.M (far exceeding the concentration used in VZV) was added to treat HCMV-infected cells, however PDX had no significant inhibitory effect on HCMV, i.e., statistically showed that HCMV-encoded gene IE1, UL44 and pp150 expression was not significantly inhibited (as shown in FIG. 4.) the results showed that 1uM Pragrexed treatment promoted cytomegalovirus-encoded gene IE1 and UL44 expression and did not affect pp150 expression.
Example 2PDX has better in vitro anti-VZV infection effect than ACV
PDX (0-1000 nM) or ACV (0 nM-100. Mu.M) was added to the VZV-infected ARPE-19 cells at various concentrations, respectively, for treatment. The effect of PDX and ACV treatment on the cell viability of ARPE-19 cells was observed by CCK-8, and as shown in FIG. 2, the half-toxic concentration of PDX (CC 50 ) CC for ACV at 27.913. Mu.M 50 > 100. Mu.M. Half-maximal Inhibitory Concentration (IC) of PDX on VZV 50 ) IC of 2.492nM for ACV versus VZV 50 2.694. Mu.M. PDX > 10000 for VZV and ACV > 37 for VZV (SI is defined as CC 50 And IC 50 Ratio (CC) 50 /IC 50 ))。
EXAMPLE 3PDX inhibits VZV infection in vivo
Male BALB/C mice of 6 weeks of age were selected and anesthetized with sodium pentobarbital for intraperitoneal injection, and the right eye was fully exposed. A "groined" scratch was made on the cornea under a split microscope with a 1mL syringe needle. Then immediately infects VZV (1X 10) 7 PFU) and assisted by gentle upper and lower eyelid (fig. 3A). After 4 hours, 1 μg/mouse was treated with PDX (dissolved in 10% dmso+40% peg300+5% Tween80+45% PBS), subconjunctival injection. 1 time a day for 3 consecutive days. Body weight information was collected and recorded from day 0 to day 7 (fig. 3C). On day 7, the corneal surface was observed with an ASX operating microscope, and corneal fluorescein staining was performed with cobalt blue light to determine the damage to the corneal surface (fig. 3D), and Optical Correlation Tomography (OCT) was used to observe the integrity and thickness of the cornea (fig. 3E). Cornea was obtained on day 7Tissue to detect mRNA expression of ORF61, H&E staining was used to observe the inflammatory infiltrate of the cornea (fig. 3B). As a result, PDX treatment was found to significantly inhibit VZV infection in the mouse cornea and did not cause inflammation of the mouse cornea tissue.
Claims (8)
1. Use of pramipexole in the manufacture of a medicament for the treatment of a varicella zoster virus caused disease, wherein the varicella zoster virus caused disease is varicella, shingles, varicella zoster virus encephalitis, varicella zoster virus conjunctivitis.
2. The use according to claim 1, wherein pramipexole inhibits replication of varicella zoster virus.
3. The use according to claim 1, wherein the pramipexole is the only active ingredient in the medicament.
4. The use according to claim 1, wherein the medicament is an oral or injectable formulation.
5. The use according to claim 4, wherein the medicament is an injection.
6. The use according to claim 1, wherein the medicament is an external preparation.
7. The use according to claim 6, wherein the medicament is an eye drop, a cream, a lotion or a gel.
8. The use according to any one of claims 1-7, wherein the medicament further comprises a pharmaceutically acceptable adjuvant.
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| WO2021189517A1 (en) * | 2020-03-23 | 2021-09-30 | 清华大学 | Use of mthfd1 inhibitor in inhibiting and killing viruses |
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| WO2021189517A1 (en) * | 2020-03-23 | 2021-09-30 | 清华大学 | Use of mthfd1 inhibitor in inhibiting and killing viruses |
Non-Patent Citations (1)
| Title |
|---|
| 黄祯祥主编.《中国医学百科全书 病毒学》.上海科学技术出版社,1992,(第1992年9月第1版，1992年12月第1次印刷版),第89页. * |
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