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Rational design of an anti-cancer peptide inhibiting CD147 / Cyp A interaction
Zahra Maani1, Safar Farajnia2, Leila Rahbarnia3
1Department of Cellular and Molecular Biology, Faculty of Science Faculty, Azarbaijan Shahid Madani University, Tabriz, Iran.
Abstract:
The CD147 / Cyp A interaction is a critical pathway in cancer types and an essential factor in entering the COVID-19 virus into the host cell. Melittin acts as an inhibitory peptide in cancer types by blocking the CD147/ Cyp A interaction. The clinical application of Melittin is limited due to weak penetration into cancer cells. TAT is an arginine-rich peptide with high penetration ability into cells widely used in drug delivery systems. This study aimed to design a hybrid peptide derived from Melittin and TAT to inhibit CD147 /Cyp A interaction. An amino acid region with high anti-cancer activity in Melittin was selected based on the physicochemical properties. Based on the results, a truncated Melittin peptide with 15 amino acids by the GGGS linker was fused to a TAT peptide (nine amino acids) to increase the penetration rate into the cell. A new hybrid peptide analog(TM) was selected by replacing the glycine with serine based on random point mutation. Docking results indicated that the TM peptide acts as an inhibitory peptide with high binding energy when interacting with CD147 and the CypA proteins. RMSD and RMSF results confirmed the high stability of the TM peptide in interaction with CD147. Also, the coarse-grained simulation showed the penetration potential of TM peptide into the DOPS-DOPC model membrane. Our findings indicated that the designed multifunctional peptide could be an attractive therapeutic candidate to halter tumor types and COVID-19 infection.
Insights
A novel hybrid peptide, TM, combines Melittin and TAT to inhibit CD147/CypA interactions, offering a potential therapeutic for cancer and COVID-19 by enhancing cell penetration.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- The CD147/CypA interaction is crucial for cancer progression and viral entry, including SARS-CoV-2.
- Melittin inhibits this interaction but has poor cell penetration, limiting its clinical use.
- TAT peptide enhances cellular uptake, making it valuable for drug delivery.
Purpose of the Study:
- To design a hybrid peptide combining Melittin and TAT to inhibit CD147/CypA interaction.
- To enhance the therapeutic potential of Melittin by improving its cell penetration.
- To evaluate the inhibitory and stability characteristics of the designed peptide.
Main Methods:
- Selection of an active Melittin region and fusion with TAT peptide via a GGGS linker.
- Design of a hybrid peptide analog (TM) through random point mutation.
- In silico analysis including molecular docking, RMSD, RMSF, and coarse-grained simulations.
Main Results:
- The TM peptide demonstrated strong binding affinity and inhibitory activity against CD147 and CypA.
- Molecular dynamics simulations confirmed the high stability of the TM peptide's interaction with CD147.
- Coarse-grained simulations indicated significant cell membrane penetration potential for the TM peptide.
Conclusions:
- The designed multifunctional TM peptide effectively inhibits CD147/CypA interaction.
- TM peptide shows promise as a therapeutic candidate for cancer and COVID-19 treatment.
- Enhanced cell penetration and target inhibition make TM a potential drug delivery system.
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