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Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors
Anna Kwiatkowska1, Frédéric Couture1, Christine Levesque1
1Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada.
Abstract:
PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N-terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N-terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile.
Insights
Modifying a PACE4 inhibitor peptide improved its stability and activity for potential prostate cancer therapy. Protecting both ends of the peptide yielded the most promising results for in vivo use.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Prostate cancer cell proliferation is influenced by PACE4 activity.
- PACE4 inhibition is a potential therapeutic strategy for prostate cancer.
- A potent PACE4 inhibitor, the multi-Leu (ML) peptide, was previously developed.
Purpose of the Study:
- To develop N-terminal modifications of the ML peptide for in vivo administration.
- To evaluate the impact of modifications on inhibitory activity, toxicity, stability, and cell penetration.
- To identify an optimized PACE4 inhibitor for potential therapeutic applications.
Main Methods:
- Synthesis and characterization of N-terminally modified ML peptide analogues.
- Assessment of antiproliferative activity against prostate cancer cells.
- Evaluation of in vitro toxicity and stability.
- Comparison of cell penetration properties.
Main Results:
- N-terminal polyethylene glycol (PEG) modification resulted in loss of activity.
- Lipid chain attachment preserved or enhanced activity but increased toxicity.
- Protection of both peptide ends with d-Leu and 4-amidinobenzylamide yielded the most stable inhibitor.
- The dual-protected inhibitor demonstrated excellent activity and a favorable toxicity profile.
Conclusions:
- N-terminal modifications can significantly alter the properties of PACE4 inhibitors.
- Dual end-protection represents a promising strategy for developing stable and effective PACE4 inhibitors for prostate cancer treatment.
- Further investigation is warranted for in vivo efficacy studies.
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