Structure based design of inhibitory peptides targeting ornithine decarboxylase dimeric interface and in vitro
Sivashanmugam Muthukumaran1,2, K N Sulochana3, Vetrivel Umashankar1,4
1Centre for Bioinformatics, Kamalnayan Bajaj Institute for Research in Vision and Ophthalmology, Vision Research Foundation, Chennai, India.
Abstract:
Polyamine synthesis in human cells is initiated by catalytic action of Ornithine decarboxylase (ODC) on Ornithine. Elevated levels of polyamines are manifested proliferating cancer cells and are found to promote tumour cell adhesion. Di-flouro methyl orninthine is a known inhibitor of ODC, however its usage is limited due its low affinity quick clearance and incompetent cellular uptake, thus posing a need for potential inhibitors. Currently, peptides are substituting drugs, as these are highly selective, specific and potent. Hence, in this study, the interacting interfaces of native homodimeric form of ODC and its heterodimer with Antizyme were probed to design inhibitory peptides targeting ODC. The designed peptides were validated for structural fitness by extensive molecular dynamics simulations and Circular dichroism studies. Finally, these peptides were validated in Y79 retinoblastoma cells for impact on ODC activity, cytotoxicity cell cycle and cell adhesion. On collective analysis, Peptide3 (Pep 3) and Peptide4 (Pep 4) were found to be potentially targeting ODC, as these peptides showed significant decrease in intracellular polyamine levels, cell adhesion and cell cycle perturbation in Y79 cells. Thus, Pep 3 and Pep 4 shall be favourably considered as therapeutic agents for targeting ODC mediated proliferation in retinoblastoma.Communicated by Ramaswamy H. Sarma.
Insights
New peptides effectively target Ornithine decarboxylase (ODC) in retinoblastoma cells, reducing polyamine levels and inhibiting cancer cell adhesion and proliferation. These findings suggest potential new therapeutic agents for cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Polyamine synthesis, initiated by Ornithine decarboxylase (ODC), is crucial for cell proliferation and is often dysregulated in cancer.
- Elevated polyamine levels correlate with cancer cell proliferation and promote tumor cell adhesion.
- Existing ODC inhibitors like difluoromethylornithine have limitations, necessitating the development of novel therapeutic strategies.
Purpose of the Study:
- To design and validate novel peptide inhibitors targeting Ornithine decarboxylase (ODC).
- To investigate the therapeutic potential of these peptides in Y79 retinoblastoma cells by assessing their impact on ODC activity, cell proliferation, and adhesion.
Main Methods:
- Probing interacting interfaces of ODC homodimer and its heterodimer with Antizyme to design peptides.
- Extensive molecular dynamics simulations and Circular dichroism studies for structural validation.
- In vitro validation in Y79 retinoblastoma cells, assessing ODC activity, cytotoxicity, cell cycle, and cell adhesion.
Main Results:
- Designed peptides were structurally validated for fitness.
- Peptide3 (Pep 3) and Peptide4 (Pep 4) demonstrated significant potential in targeting ODC.
- These peptides led to a notable decrease in intracellular polyamine levels, reduced cell adhesion, and caused cell cycle perturbation in Y79 cells.
Conclusions:
- Peptide3 and Peptide4 show promise as therapeutic agents for targeting ODC-mediated proliferation in retinoblastoma.
- These peptides offer a potential new avenue for cancer therapy by modulating polyamine synthesis.
- Further consideration of Pep 3 and Pep 4 as therapeutic agents for retinoblastoma is warranted.
