Discovering new medicines targeting helicases: challenges and recent progress

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Helicases are motor proteins crucial for nucleic acid metabolism, utilizing adenosine triphosphate (ATP) hydrolysis.
• These enzymes are vital in bacteria, viruses, and human cells, making them significant drug targets.

Purpose of the Study:

• To review the biochemistry of frequently targeted helicases from various sources.
• To discuss assays, inhibitor chemotypes, and challenges in helicase inhibitor discovery.

Main Methods:

• Literature review of viral, bacterial, and human helicases.
• Summary of established and emerging helicase inhibitor discovery assays.
• Analysis of common helicase inhibitor classes and their mechanisms.

Main Results:

• Identified key viral (HSV, HPV, Polyomavirus, Coronavirus, HCV, Flavivirus), bacterial (DnaB-like, RecBCD-like), and human (DDX3, RecQ-like, eIF4A) helicase targets.
• Detailed common helicase inhibitor chemotypes including nucleotide analogs, polyphenyls, and flavones.
• Highlighted challenges and potential solutions in developing potent helicase inhibitors.

Conclusions:

• Targeting helicases offers a promising strategy for developing novel antiviral, antibiotic, and anticancer drugs.
• Understanding helicase biochemistry and inhibitor landscapes is crucial for successful drug development.
• Continued research into helicase inhibitor chemotypes and overcoming discovery challenges is warranted.