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Published on: March 8, 2012
Identification of a peptide that disrupts hADA3-E6 interaction with implications in HPV induced cancer therapy
Vaibhav Chand1, Abhijeet Kapoor1, Suman Kundu1
1Department of Biochemistry, University of Delhi South Campus, New Delhi 110021, India.
Aim:
High risk Human Papillomavirus (HPV) is an infectious pathogen implicated in a variety of cancers with poor clinical outcome. The mechanism of HPV induced cellular transformation and its intervention remains to be elucidated. Human ADA3 (hADA3), a cellular target of HPV16 E6, is an essential and conserved component of the ADA transcriptional coactivator complex. High risk HPV-E6 binds and functionally inactivates hADA3 to initiate oncogenesis. The aim of this study was to identify the interaction interface between hADA3 and HPV16E6 for designing inhibitory peptides that can potentially disrupt the hADA3-E6 interaction.
Material Methods:
The present investigation employed structure-based in silico tools supported by biochemical validation, in vivo interaction studies and analysis of posttranslational modifications.
Key Findings:
First 3D-model of hADA3 was proposed and domains involved in the oncogenic interaction between hADA3 and HPV16E6 were delineated. Rationally designed peptide disrupted hADA3-E6 interaction and impeded malignant properties of cervical cancer cells.
Significance:
Intervention of hADA3-E6 interaction thus promises to be a potential strategy to combat HPV induced oncogenic conditions like cervical cancer. The investigation provides mechanistic insights into HPV pathogenesis and shows promise in developing novel therapeutics to treat HPV induced cancers.
Insights
Targeting the interaction between Human Papillomavirus (HPV) oncoprotein E6 and human ADA3 (hADA3) protein can combat cervical cancer. A rationally designed peptide disrupted this interaction, impeding cancer cell malignancy.
Area of Science:
- Oncology
- Virology
- Molecular Biology
Background:
- High-risk Human Papillomavirus (HPV) is linked to cancers with poor outcomes.
- The oncogenic mechanism of HPV, particularly the role of HPV16 E6 in targeting human ADA3 (hADA3), requires further elucidation.
- hADA3 is a crucial component of the ADA transcriptional coactivator complex, essential for cellular function.
Purpose of the Study:
- To identify the specific interaction interface between hADA3 and HPV16 E6.
- To design inhibitory peptides capable of disrupting the hADA3-E6 interaction for therapeutic purposes.
Main Methods:
- Utilized structure-based in silico tools for modeling.
- Performed biochemical validation and in vivo interaction studies.
- Analyzed posttranslational modifications to understand the interaction dynamics.
Main Results:
- Developed the first 3D model of hADA3, delineating key domains in the oncogenic interaction with HPV16 E6.
- A rationally designed peptide successfully disrupted the hADA3-E6 interaction.
- The peptide treatment impeded the malignant properties of cervical cancer cells.
Conclusions:
- Disrupting the hADA3-E6 interaction presents a promising therapeutic strategy against HPV-induced cancers, such as cervical cancer.
- The study offers mechanistic insights into HPV pathogenesis.
- This research paves the way for novel therapeutics targeting HPV-induced oncogenic conditions.
