Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• DNA-encoded libraries (DELs) are powerful tools for small molecule discovery.
• Conventional small molecule libraries have limitations in diversity and efficiency.
• Advancements in DEL synthesis are crucial for expanding their utility.

Purpose of the Study:

• To streamline and enhance DNA-encoded and DNA-templated library synthesis.
• To increase the structural diversity and drug-likeness of library members.
• To develop a cost-effective and efficient platform for bioactive small molecule discovery.

Main Methods:

• Developed and validated a large set of orthogonal codons for library construction.
• Employed chemical and computational tools to improve library member diversity and drug-likeness.
• Utilized a polymerase-mediated strategy for efficient template library assembly.
• Implemented advanced library isolation and purification techniques.

Main Results:

• Created a second-generation DNA-templated library of 256,000 small-molecule macrocycles.
• The synthesized library exhibited improved drug-like physical properties.
• In vitro selection identified novel insulin-degrading enzyme inhibitors, including a potent macrocycle (IC50 = 40 nM).

Conclusions:

• The enhanced methods provide a more powerful and accessible platform for DNA-templated library synthesis.
• Streamlined processes make DNA-templated libraries more cost-effective for bioactive molecule discovery.
• These advancements significantly improve the utility of DNA-templated libraries in drug discovery efforts.