Lipophilic compound conjugates of cell-penetrating peptides and their application in antibacterial

A technology that penetrates peptides and compounds, and is applied in the direction of antibacterial drugs, antifungal agents, peptide preparation methods, etc., and can solve the problems of enhanced host immune system resistance, bacterial drug resistance, difficult treatment of infectious diseases, and difficult disease treatment, etc. question

Active Publication Date: 2020-09-29
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

These increasing bacterial drug resistance problems and increasingly complex drug resistance mechanisms have brought great difficulties to the treatment of related diseases, and have even seriously endangered the health and lives of patients.
[0005] At the same time, the bacteria existing in the form of biofilm have significantly enhanced resistance to antibacterial drugs, external environmental pressure and host immune system, which is also one of the important reasons leading to bacterial drug resistance and difficult treatment of infectious diseases

Method used

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  • Lipophilic compound conjugates of cell-penetrating peptides and their application in antibacterial
  • Lipophilic compound conjugates of cell-penetrating peptides and their application in antibacterial
  • Lipophilic compound conjugates of cell-penetrating peptides and their application in antibacterial

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0083] Embodiment 1, the preparation of lipopeptide

[0084] In this example, six lipopeptides named C4-TAT, C8-TAT, C12-TAT, C14-TAT, C16-TAT and C20-TAT were prepared, all of which were penetrated by cells named TAT Peptide (amino acid sequence is YGRKKRRQRRR ie SEQ ID No. 1), which is formed by linking lipophilic compound connected to the amino terminus of the cell penetrating peptide.

[0085] The structural formula of C4-TAT is: C4-YGRKKRRQRRR, wherein C4 is butyric acid;

[0086] The structural formula of C8-TAT is: C8-YGRKKRRQRRR, wherein C8 is octanoic acid;

[0087] The structural formula of C12-TAT is: C12-YGRKKRRQRRR, wherein C12 is lauric acid;

[0088] The structural formula of C14-TAT is: C14-YGRKKRRQRRR, wherein, C14 is myristic acid;

[0089] The structural formula of C16-TAT is: C16-YGRKKRRQRRR, wherein, C16 is palmitic acid;

[0090] The structural formula of C20-TAT is: C20-YGRKKRRQRRR, wherein C20 is arachidic acid;

[0091] YGRKKRRQRRR in the structur...

Embodiment 2

[0095] Embodiment 2, the antibacterial action of lipopeptide

[0096] 1. Determination of minimum inhibitory concentration (MIC)

[0097] Adopt plate double dilution method to carry out drug susceptibility test, measure the minimum inhibitory concentration (MIC) of C4-TAT, C8-TAT, C12-TAT, C14-TAT, C16-TAT and C20-TAT in embodiment 1, specifically The experimental method is as follows: the test bacteria (as shown in Table 2) were cultured with MH broth medium. Drugs (C4-TAT, C8-TAT, C12-TAT, C14-TAT, C16-TAT and C20-TAT in Example 1) are diluted into various required concentrations with MH broth medium twice, and an appropriate amount is added respectively In the petri dish, the MH agar medium is quantitatively injected into the petri dish containing the medicine after melting, and mixed evenly, and various tested microorganisms are inoculated with a multi-point inoculator, (the inoculum size is 10 4 CFU / spot) was placed in a 37°C incubator for 18 hours of constant temperatu...

Embodiment 3

[0120] Embodiment 3, combined application of lipopeptide and antibacterial drug

[0121] 1. Determination of combined use index (FIC) of lipopeptide and antibacterial drugs against drug-resistant bacteria

[0122] Measure respectively the FIC value of the lipopeptide C12-TAT of embodiment 1 and antimicrobial drug combined application to Gram-positive drug-resistant bacterium Staphylococcus aureus ATCC33591 (MRSA), and the C16-TAT of embodiment 1 and antibacterial drug combined application to FIC values ​​of Gram-negative drug-resistant bacteria Pseudomonas aeruginosa ATCC 27853. The method and results are as follows:

[0123] Each antimicrobial drug (as drug A) and lipopeptide (as drug B) respectively took their respective 2MIC as the highest concentration, diluted to 8 concentrations with sterile MH broth medium, respectively, along the horizontal axis of the microwell culture plate, Add 50 μL of MH broth medium containing different concentrations of the two drugs on the ve...

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Abstract

The invention discloses a lipophilic compound conjugate of a cell penetrating peptide and its application in antibacterial. The lipophilic compound conjugate of the cell penetrating peptide is formed by linking the cell penetrating peptide with a lipophilic compound connected to the amino terminus or carboxyl terminus of the cell penetrating peptide. The lipophilic compound conjugate of the antibacterial peptide has good inhibitory and killing effects on Gram-positive bacteria, Gram-negative bacteria and fungi, and has broad-spectrum antibacterial effect. Among them, C12‑TAT combined with clarithromycin has an additive effect in inhibiting methicillin-resistant Staphylococcus aureus; C12‑TAT combined with imipenem has an obvious synergistic effect. In terms of inhibiting Pseudomonas aeruginosa, C16‑TAT combined with clarithromycin has an additive effect; C16‑TAT combined with imipenem has an obvious synergistic effect.

Description

technical field [0001] The invention relates to a lipophilic compound conjugate of a cell penetrating peptide in the field of antibacterial and its application in antibacterial. Background technique [0002] Antibiotics have always been the main drug for clinical anti-infection treatment. The great success of antibiotics from the 1940s to the 1970s has reduced the attention and investment in the research and development of antibacterial drugs. In the past 40 years, the research and development of anti-drug-resistant bacteria in the world has been slow. Mechanisms and drugs with new targets are rarely launched, and known effective drugs (or their derivatives) have been repeatedly used or even abused for many years, resulting in a decline in drug efficacy and drug resistance. [0003] The growing problem of bacterial resistance to antibiotics has received widespread attention worldwide. Due to the continuous emergence of resistant strains of various antibacterial drugs, the t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K7/06C07K1/06A61K38/08A61K31/407A61K31/7048A61P31/04A61P31/10
CPCA61K38/08A61K31/407A61K31/7048A61P31/04A61P31/10A61K2300/00Y02P20/55
Inventor 李桂玲李馨儒于菲菲侯续成张文茜周文凯孟艳莎
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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