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Button-Push On-Demand Synthesis for Rapid Optimization of Antiviral Peptidomimetics
Duanshuai Tian1, Ting Wei Tan1, Ronald Toh Kuan Hai2
1Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543.
Journal of the American Chemical Society
|October 30, 2024
Summary
Automated solid-phase flow synthesis rapidly generates diverse peptidomimetics for drug discovery. This platform accelerates the identification of potent broad-spectrum antiviral drug candidates, improving efficiency and reducing synthesis challenges.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Drug Discovery
Background:
- Drug candidate optimization is crucial but hindered by manual synthesis.
- Automated synthesis faces challenges in multistep reactions due to incompatibilities and side-products.
Purpose of the Study:
- To develop an automated solid-phase flow platform for synthesizing α-keto-amides and nitrile peptidomimetics.
- To identify potent broad-spectrum antiviral leads using this platform and docking simulations.
Main Methods:
- Construction of a compact parallel synthesizer for automated synthesis.
- Generation of 42 derivatives for structure-activity relationship (SAR) studies.
- Utilized docking simulations to guide compound design.
Main Results:
- Synthesized 42 novel peptidomimetic derivatives in three months.
- Identified ten derivatives with high target inhibitory activity (IC50 < 100 nM).
- Discovered two derivatives with significant broad-spectrum antiviral activity (EC50 < 250 nM).
Conclusions:
- The automated solid-phase flow platform provides rapid access to diverse peptidomimetics.
- This approach accelerates the discovery of complex molecular scaffolds for antiviral drug candidates.
- Integration with medicinal chemistry campaigns shows potential to revolutionize drug discovery paradigms.
