Discovery and structure-based optimization of adenain inhibitors

Area of Science:

• Virology
• Structural Biology
• Medicinal Chemistry

Background:

• Adenain is a crucial cysteine protease in adenoviruses, making it a significant target for antiviral therapies.
• Adenoviral infections can cause ocular diseases and other health issues, necessitating the development of effective treatments.

Purpose of the Study:

• To identify and develop novel inhibitors targeting the adenain protease.
• To elucidate the binding mechanisms of inhibitors with adenain through structural analysis.
• To optimize initial hits into potent, drug-like compounds for potential therapeutic applications.

Main Methods:

• Employed a two-pronged hit discovery approach to identify initial inhibitor candidates.
• Determined high-resolution X-ray cocrystal structures of adenain complexed with identified inhibitors.
• Utilized a structure-guided medicinal chemistry strategy for inhibitor optimization.

Main Results:

• Identified tetrapeptide nitrile 1 and pyrimidine nitrile 2 as complementary starting points for adenain inhibition.
• Obtained the first high-resolution X-ray cocrystal structures revealing the binding modes of inhibitors 1 and 2.
• Optimized screening hits into low nanomolar, drug-like inhibitors of adenain.

Conclusions:

• The identified inhibitors represent promising leads for the development of novel antiviral drugs against adenoviral infections.
• Structural insights into inhibitor binding facilitate further drug design and optimization.
• The developed compounds show potential for treating ocular and other adenoviral diseases.