Small Molecule Inhibition of Mononegavirales RNA Polymerases

Area of Science:

• Virology
• Structural Biology
• Medicinal Chemistry

Background:

• The order Mononegavirales comprises non-segmented negative-sense RNA viruses, many of which are significant human pathogens.
• Viral transcription and replication rely on the multifunctional RNA-dependent RNA polymerase (L protein).
• Cryo-electron microscopy (cryo-EM) has recently provided structural insights into these viral polymerases.

Purpose of the Study:

• To review current developments in small-molecule inhibition of Mononegavirales polymerases.
• To explore nucleoside/nucleotide and non-nucleoside inhibitors targeting conserved pockets within the L protein.
• To highlight opportunities for broad-spectrum antiviral drug design against Mononegavirales pathogens.

Main Methods:

• Review of recent biochemical and structural findings on Mononegavirales L protein inhibitors.
• Analysis of cryo-EM data elucidating polymerase structures and inhibitor interactions.
• Identification of conserved druggable pockets within the L protein.

Main Results:

• Small molecules can inhibit Mononegavirales polymerases by targeting either the catalytic site (nucleoside/nucleotide inhibitors) or allosteric pockets (non-nucleoside inhibitors).
• Structural studies reveal conserved druggable pockets across different Mononegavirales L proteins.
• These conserved pockets represent promising targets for antiviral drug development.

Conclusions:

• Small-molecule inhibitors targeting the L protein offer a viable strategy for developing broad-spectrum antivirals against Mononegavirales.
• Understanding the structural basis of inhibitor binding facilitates rational drug design.
• Further research into these conserved pockets could lead to effective treatments for Mononegavirales infections.