Small molecule inhibitors of the human papillomavirus E1-E2 interaction

Area of Science:

• Virology
• Molecular Biology
• Drug Discovery

Background:

• Human papillomaviruses (HPV) cause diseases like cervical cancer and genital warts.
• Low-risk HPV types 6 and 11 are associated with genital warts.
• Targeting viral DNA replication is a potential strategy against HPV.

Purpose of the Study:

• To discover inhibitors of HPV DNA replication.
• To identify compounds that disrupt the interaction between HPV E1 and E2 proteins.

Main Methods:

• High-throughput screening for inhibitors of viral DNA replication.
• Biochemical and biophysical assays to study protein-protein interactions.
• Cocrystallization and structure-activity relationship (SAR) studies.

Main Results:

• Two novel series of compounds inhibiting the HPV E1-E2 interaction were identified.
• Compounds bind to overlapping sites on the E2 transactivation domain.
• Structure-activity investigations yielded compounds with low nanomolar activity against the HPV11 E1-E2 interaction.
• Cellular assays showed EC50 values around 1 μM for DNA replication inhibition.

Conclusions:

• Discovery of potent inhibitors targeting the HPV E1-E2 protein-protein interaction.
• Compounds demonstrate potential for therapeutic development against HPV infections.
• Insights gained into the discovery of protein-protein interaction inhibitors.