Large Libraries of Structurally Diverse Macrocycles Suitable for Membrane Permeation.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Macrocycles are promising drug candidates due to strong binding and cell permeability.
• Current methods often use invariant thiol-containing amino acids, limiting diversity and increasing size.

Purpose of the Study:

• To develop novel, structurally diverse macrocyclic peptides using variable thiol-containing elements.
• To create a large combinatorial library of macrocycles with enhanced skeletal complexity.
• To identify potent inhibitors of thrombin and plasma kallikrein with favorable membrane permeability.

Main Methods:

• Synthesized diverse thiol-containing building blocks.
• Constructed a 2,688-member combinatorial library of peptidic macrocycles.
• Screened the library for enzyme inhibitors and assessed membrane permeability.
• Utilized X-ray crystallography to analyze macrocycle-target interactions.

Main Results:

• Successfully synthesized a library of structurally complex macrocycles.
• Discovered potent inhibitors of thrombin and plasma kallikrein.
• Identified compounds with favorable membrane permeability.
• X-ray analysis confirmed the importance of thiol element size and shape for binding.

Conclusions:

• The new strategy significantly enhances structural diversity in macrocyclic peptide libraries.
• This approach allows combinatorial modification of previously invariant regions.
• The developed macrocycles show potential for creating membrane-permeable therapeutics.
• This method can be broadly applied in drug development for various targets.