Artificial peptidomimetic as well as preparation method and application thereof

An artificial and pharmaceutical preparation technology, applied in the field of biomedicine, can solve problems such as heavy economic burden, and achieve the effects of easy industrialization, simple preparation process, and reasonable selection of raw materials

Active Publication Date: 2021-06-25
WUHAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, RA patients need long-term medication, and the drugs have certain side effects, such as long-term use of non-steroidal anti-inflammatory drugs can induce oral ulcers, drug-induced liver injury (abnormally elevated liver enzymes), abdominal pain, diarrhea, nausea and other symptoms; Long-term use of glucocorticoids in RA patients can increase the risk of cardiovascular disease, diabetes, infection, etc., and have an impact on bone development; antirheumatic drugs, such as methotrexate, have gastrointestinal reactions (mainly manifested as nausea, Vomiting, diarrhea, etc.), bone marrow suppression (leukopenia, skin or internal bleeding), kidney damage and other adverse reactions; biological agents such as infliximab have occurred in clinical trials such as skin rash, headache, nausea, respiratory tract infection, abnormal blood pressure, Adverse events such as elevated transaminases, and the medical expenses of patients using biological agents are 3-5 times the average treatment expenses of the disease, and the economic burden is heavy; herbal preparations, such as tripterygium glycosides tablets, also have vomiting, fatigue, and loss of appetite , abdominal distension, elevated transaminases, white blood cells, thrombocytopenia, oliguria or polyuria, edema, abnormal renal function, palpitations, chest tightness, arrhythmia, dizziness, dizziness and other adverse reactions

Method used

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  • Artificial peptidomimetic as well as preparation method and application thereof
  • Artificial peptidomimetic as well as preparation method and application thereof
  • Artificial peptidomimetic as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1: Leading peptidomimetic intermediate DGRC-COOC 2 h 5 preparation of

[0060] Leading peptoid intermediate DGRC-COOC 2 h 5 The structural formula is as shown in formula 2:

[0061]

[0062] Concrete preparation steps are as follows:

[0063] In the preparation of the leading peptidomimetic intermediate, 9-fluorenylmethoxycarbonyl (FMOC) was used as the amino-terminal protecting group, and 4-(2′,4′-dimethoxyphenyl-fluorenylmethoxycarbonyl-aminomethyl base)-phenoxyacetamido-methylbenzhydrylamine resin (Rinkamide MBHA resin) as the solid phase carrier, the condensing agent is 1-hydroxybenzotriazole / dicyclohexylcarbodiimide (HOBt / DCC), The peptide chain is extended from the carboxyl terminal to the amino terminal, and the natural amino acids aspartic acid, glycine, and arginine are sequentially connected. Finally, carboxyacetylated non-natural cysteine ​​is used as a raw material, and its amino group forms an amide bond with the carboxyl group at the R-ter...

Embodiment 2

[0064] Example 2: Preparation of natural truncated peptidomimetic intermediate HCONH-CYPRKR

[0065] The structural formula of the natural truncated peptidomimetic intermediate HCONH-CYPRKR is shown in formula 3 below:

[0066]

[0067]Concrete preparation steps are as follows:

[0068] In the preparation of natural truncated peptidomimetic intermediates, 9-fluorenylmethoxycarbonyl (FMOC) was used as the amino-terminal protecting group, and 4-(2′,4′-dimethoxyphenyl-fluorenylmethoxycarbonyl -Aminomethyl)-phenoxyacetamido-methylbenzhydrylamine resin (Rink amide MBHA resin) is a solid phase carrier, and the condensation agent is 1-hydroxybenzotriazole / dicyclohexylcarbodiimide (HOBt / DCC), extending the peptide chain from the carboxy-terminus to the amino-terminus, first using carbamylated cysteine ​​as the raw material, and then successively connecting tyrosine, proline, arginine, lysine and arginine acid. Use mass percent (m / m) as the mixed solution of 96% trifluoroacetic ...

Embodiment 3

[0069] Embodiment 3: the synthesis of artificial peptidomimetic

[0070] The structural formula of the artificial peptidomimetic is shown in formula 1 below:

[0071]

[0072] The specific synthesis steps are as follows: the leading peptidomimetic intermediate DGRC-COOC prepared in the above-mentioned Example 1 and Example 2 2 h 5 And natural truncated peptidomimetic intermediate HCONH-CYPRKR as raw material. Take 10mg of the leading peptidomimetic intermediate and 18mg of the natural truncated peptidomimetic intermediate in a 50mL brown blue cap reagent bottle (the molar mass ratio of the two is about 1:1), add 25mL of Tris with a concentration of 0.1M pH=7.1 - HCl buffer. Tighten the bottle cap and seal it with Pharfim sealing film. After confirming that there is no leakage, invert the reagent bottle to speed up the dissolution of the peptide. Place the reagent bottle containing the leading peptidomimetic intermediate and natural truncated peptidomimetic intermediate ...

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Abstract

The invention provides an artificial peptidomimetic. The structural formula of the artificial peptidomimetic is as shown in formula 1. The invention also provides a preparation method and application of the artificial peptidomimetic. The preparation method provided by the invention is reasonable in raw material selection, easy to obtain, simple in preparation process and easy to industrialize. The artificial peptidomimetic provided by the invention can be used for preparing medicines for preventing or treating redness and swelling of joints or/and swelling of joints or/and bone erosion of joints or/and joint deformation or/and reduction of joint bone density, and can also be used for preparing medicines for preventing or treating and inhibiting inflammation-related cytokines IL-1beta or/and IL-8 or/and TNF-alpha.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular to an artificial peptide and its preparation method and application. Background technique [0002] Rheumatoid arthritis (rheumatoid arthritis, RA) is a chronic systemic autoimmune disease, mainly causing joint tenderness, swelling and destruction, resulting in disability. The disease is prone to occur in women, and the age is mainly concentrated between 30-50 years old. Worldwide, about 1% of the population suffers from the disease. The lesions of RA are mostly small joints, which have the characteristics of symmetrical distribution. The early clinical symptoms are mainly redness, pain, and limited range of motion. As the disease progresses, the joint mobility gradually decreases, and some patients lose their joint mobility completely. . If the condition is not well controlled, RA may also lead to organ involvement other than joints, such as: keratitis, rheumatoid nodules, pericarditis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/37C07K5/113C07K1/06C07K1/04A61K38/16A61P19/02A61P29/00
CPCC07K14/37C07K5/1021A61P19/02A61P29/00A61K38/00Y02P20/55
Inventor 沈秉正孟兰霞王敏兰昱张孟科吕丰朱占永周炎金琼琼
Owner WUHAN UNIV
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