Developing New Strategies to Construct Pseudo-natural Macrocycles for Undruggable Targets

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Up to 85% of disease-related target proteins are undruggable, hindering therapeutic interventions.
• Macrocyclic compounds, particularly molecular glues, show promise for modulating these targets.
• Current macrocyclic drugs often originate from natural products, posing challenges in synthesis and availability.

Purpose of the Study:

• To develop innovative methodologies for constructing pseudo-natural macrocycles.
• To create a diverse library of pseudo-natural macrocycles for modulating undruggable targets.
• To highlight a modular biomimetic assembly strategy for rapid macrocycle generation.

Main Methods:

• Deconstructing natural product biosynthetic logic into programmable building blocks.
• Developing novel reactions to mimic natural bioactive building blocks.
• Replacing intricate chiral motifs with readily available amino acid derivatives.

Main Results:

• A modular biomimetic strategy enables rapid generation of diverse pseudo-natural macrocycles.
• Demonstrated applications include macrocyclic oximes for anti-influenza, spiro-fused macrocycles for Parkinson's disease, and macrocycles targeting protein-protein interactions for multidrug resistance.
• Structurally diverse, multifunctional bioactive pseudo-natural macrocycles can be produced concisely and sustainably.

Conclusions:

• The modular biomimetic strategy offers a sustainable and efficient approach to synthesize pseudo-natural macrocycles.
• This strategy holds significant potential for modulating undruggable targets and advancing drug discovery.
• Continued efforts in organic synthesis-driven medicinal chemistry can provide practical solutions for critical drug discovery challenges.