First Mariner Mos1 transposase inhibitors

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Mos1 is a transposon, a mobile genetic element.
• Transposons and viral integrases share similarities in their mechanisms.
• Inhibiting these enzymes is crucial for understanding genome stability and developing antiviral therapies.

Purpose of the Study:

• To identify novel chemical inhibitors of Mos1 transposition.
• To explore the potential of Mos1 transposase as a surrogate for screening HIV-1 integrase inhibitors.

Main Methods:

• Chemical synthesis of novel compounds based on a bis-(heteroaryl)maleimides scaffold.
• Assay of compound activity against Mos1 transposition.
• Evaluation of cross-activity with HIV-1 integrase.

Main Results:

• Several known inhibitors of Tn5 transposase and HIV-1 integrase also inhibited Mos1 transposition.
• Novel bis-(heteroaryl)maleimides were identified as potent Mos1 inhibitors.
• The mechanism of action varied based on chemical substitutions on the maleimide scaffold.
• Significant cross-activity was observed between HIV-1 integrase and Mos1 transposase inhibition.

Conclusions:

• Mos1 transposase can be effectively inhibited by small molecules.
• Bis-(heteroaryl)maleimides represent a promising scaffold for developing Mos1 inhibitors.
• Mos1 transposase serves as a valuable surrogate for high-throughput screening of HIV-1 integrase inhibitors, potentially accelerating antiviral drug discovery.