An Alternative Solution for Peptide Drug Development
Issue:
Volume 8, Issue 4, December 2022
Pages:
46-49
Received:
4 October 2022
Accepted:
21 October 2022
Published:
28 October 2022
DOI:
10.11648/j.jddmc.20220804.11
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Abstract: Polypeptide molecules are now a significant source of new chemical entities in the pharmaceutical industry. When exploring structure activity relationships of potential peptide sequences for various targeted receptors, medicinal chemists often encounter structures which have the desired affinity and specificity for the target, but which are intractable as potential drug molecules because of problems related to solubility or chemical stability. Significant cost and time are added to development cycles though the process of exploring alternative structures that will overcome such problems. A more expeditions approach to enabling a candidate molecule to be formulated as a drug would offer significant benefits in cost and time savings. Herein we introduce a novel concept for resolution of stability and solubility problems confronting formulators working with peptide drug molecules. Aprotic solvents such as Dimethyl Sulfoxide are shown to be safe and effective solvents for injectable peptide drugs, and are shown to offer long term shelf stability for such molecules in liquid formulations. The aprotic solvent technology obviates the need for costly and time consuming lyophilization processes. Its ability to increase solubility while obviating pH effects enables delivery of well tolerated small volume therapeutic doses. The technology also obviates the effect of pH and coupled with its ability to increase the concentration of peptide, affords a parenteral dose volume that is reduced and which spares the patient exposure to irritation that can be introduced by pH outside the range of neutrality.
Abstract: Polypeptide molecules are now a significant source of new chemical entities in the pharmaceutical industry. When exploring structure activity relationships of potential peptide sequences for various targeted receptors, medicinal chemists often encounter structures which have the desired affinity and specificity for the target, but which are intract...
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The Study of Cyclic Analogues of Carnosine Peptide on Isolated Mitochondria of A549 Cells
Mohammadreza Gholibeikian,
Nastaran Gholami Samali,
Amirreza Arvaneh
Issue:
Volume 8, Issue 4, December 2022
Pages:
50-56
Received:
8 October 2022
Accepted:
9 November 2022
Published:
31 January 2023
Abstract: Bachground & Aims: In this work a various range of toxicity on A549 cells was resulted by the cyclic Carnosine analogues using MTT assay. The purpose of this research was to study the effects of analogues Carnosine peptide on A549 cells using several experiments. Also, applying peptides on the mitochondria of A549 cells, a raise of mitochondrial reactive oxygen species (ROS) level, mitochondrial swelling, mitochondrial membrane potential (ψm) collapse, release of cytochrome c of the affected mitochondria were detected. Methods: For determination of Cytotoxicity, Normal calls and A549 cancerous cells (1×107/well) were transferred into 96-well plates and treated with 10 μg/mL concentration of Carnosine analogues for 12h. The effect of peptides on the activity of SDH was assayed by MTT test. 100 μL mitochondrial suspensions from A549 and normal groups were incubated with applied concentration of peptides (10μg/mL) at 37°C for 30 min. The fluorescence intensity of DCFH which is an indicator of ROS concentration was then assayed by a Shimadzu RF-5000U fluorescence spectrophotometer. Mitochondrial accumulation and also redistribution of the cationic fluorescent dye, Rhoda mine 123 (Rh 123, concentration, 10 µM), from mitochondria into the cytosol have been used for the determination of MMP collapse. Mitochondria from A549 and normal groups were suspended in corresponding assay buffer and incubated at 37°C with 10µg/mL peptides. The release of Cytochrome c by peptides was assayed by the Quantikine Cytochrome c. Results: The results showed that all the synthesized cyclic peptides increased ROS in various levels in comparison with unaffected mitochondria isolated from A549 group. A significant increase of ROS was resulted by 2c, 4c and 6c analogues at 30 min. Rh 123 fluorescence staining indicated that the integrity of the mitochondria was damaged by the cyclic peptides. Compounds 2c, 4c and 6c significantly increased the collapse of MMP among the Carnosine analogues in comparison with mitochondria isolated from A549 group. Peptides 2c, 4c and 6c significantly increased mitochondrial swelling in comparison with untreated mitochondria isolated from the A549 group. The result was that cyclic peptides 2c, 4c and 6c significantly increased the release of cytochrome c in comparison with unaffected mitochondria isolated from the A549 group. Conclusion: Based on the overall results, cyclic analogues of Carnosine peptide, especially compounds 2c [Cyclo-(Pro-β-alanine-His-β-alanine-His)], 4c [Cyclo-(Pro-His-β-alanine-β-alanine-His)] and 6c [Cyclo-(Pro-β-alanine-His-His-β-alanine)], showed more toxic activity than other Carnosine analogues, which would be supporting to develop these peptide analogues as new anticancer and complementary therapeutic agents for the treatment of lung cancer.
Abstract: Bachground & Aims: In this work a various range of toxicity on A549 cells was resulted by the cyclic Carnosine analogues using MTT assay. The purpose of this research was to study the effects of analogues Carnosine peptide on A549 cells using several experiments. Also, applying peptides on the mitochondria of A549 cells, a raise of mitochondrial re...
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