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Published on: September 30, 2016
Identification and characterization of small molecule antagonists of pRb inactivation by viral oncoproteins
Daniela Fera1, David C Schultz, Santosh Hodawadekar
1Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, PA 19104, USA.
Abstract:
The retinoblastoma protein pRb is essential for regulating many cellular activities through its binding and inhibition of E2F transcription activators, and pRb inactivation leads to many cancers. pRb activity can be perturbed by viral oncoproteins including human papillomavirus (HPV) that share an LxCxE motif. Because there are no treatments for existing HPV infection leading to nearly all cervical cancers and other cancers to a lesser extent, we screened for compounds that inhibit the ability of HPV-E7 to disrupt pRb/E2F complexes. This lead to the identification of thiadiazolidinedione compounds that bind to pRb with mid-high nanomolar dissociation constants, are competitive with the binding of viral oncoproteins containing an LxCxE motif, and are selectively cytotoxic in HPV-positive cells alone and in mice. These inhibitors provide a promising scaffold for the development of therapies to treat HPV-mediated pathologies.
Insights
Researchers identified thiadiazolidinedione compounds that block human papillomavirus (HPV) oncoproteins from disrupting cellular regulators. These compounds show promise for treating HPV-related cancers.
Area of Science:
- Molecular Biology
- Oncology
- Virology
Background:
- The retinoblastoma protein (pRb) regulates cell activity by inhibiting E2F transcription factors.
- Viral oncoproteins, such as human papillomavirus (HPV) E7, can inactivate pRb via an LxCxE motif, contributing to cancer development.
- Current treatments for HPV infection and associated cancers are limited.
Purpose of the Study:
- To screen for compounds that inhibit the interaction between HPV-E7 oncoprotein and the pRb/E2F complex.
- To identify potential therapeutic agents for HPV-mediated pathologies.
Main Methods:
- Screening for compounds that disrupt the HPV-E7 oncoprotein's ability to bind to pRb.
- Characterizing the binding affinity and competitive inhibition of identified compounds.
- Evaluating the selective cytotoxicity of lead compounds in HPV-positive cells and in vivo mouse models.
Main Results:
- Identification of thiadiazolidinedione compounds as inhibitors of HPV-E7 binding to pRb.
- These compounds exhibit mid-to-high nanomolar dissociation constants for pRb.
- The identified inhibitors are competitive with viral oncoproteins containing the LxCxE motif.
- Selective cytotoxicity was observed in HPV-positive cells and in mouse models.
Conclusions:
- Thiadiazolidinedione compounds represent a promising scaffold for developing novel therapies against HPV-related cancers.
- These inhibitors offer a potential strategy to counteract the oncogenic effects of HPV by restoring pRb function.
- Further development of these compounds could lead to effective treatments for HPV-mediated diseases.
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