A Reverse Structure-based Design of HPV E7 Inhibitor.

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Human papillomavirus (HPV) is a DNA virus linked to over 99% of cervical cancers.
• The HPV E7 oncoprotein is crucial for cell cycle progression in infected cells by interacting with the retinoblastoma protein (pRb).
• Targeting the interaction between HPV E7 and pRb offers a potential strategy for antiviral therapy.

Purpose of the Study:

• To design a peptide inhibitor targeting the HPV E7 oncoprotein using an in silico approach.
• To evaluate the efficacy and safety of the designed peptide inhibitor in HPV-infected cell lines.

Main Methods:

• A reverse structure-based approach was employed to design peptide inhibitors targeting the LXCXE binding domain of pRb.
• In silico screening identified a 9-amino acid peptide, named peptide Y, with favorable binding interactions.
• In vitro studies included cytotoxicity assays and cell cycle analysis in CaSki (HPV-positive) and HaCaT (normal keratinocyte) cell lines.

Main Results:

• Peptide Y demonstrated low cytotoxicity, maintaining over 74% cell viability in both cell lines.
• Treatment with peptide Y led to cell cycle arrest, specifically accumulation in G0/G1 and S phases, and a reduction in G2/M phase in CaSki cells.
• No significant impact on the cell cycle was observed in normal HaCaT cells, suggesting specificity.

Conclusions:

• The designed peptide Y effectively inhibits HPV E7 by modulating the cell cycle in HPV-transformed cells.
• Peptide Y shows potential as a therapeutic agent for HPV-related cancers.
• These findings support the development of peptide-based inhibitors for HPV E7.