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Updated: Aug 14, 2025
Biosensor-based High Throughput Biopanning and Bioinformatics Analysis Strategy for the Global Validation of Drug-protein Interactions
Published on: December 1, 2020
Combining high throughput array synthesis and growth algorithm to discover TNF-α binders with new structures and
Weilin Lin1, Shanil Gandhi2, Prabesh Bhattarai3
1B CUBE Center for Molecular Bioengineering, Technische Universität Dresden, Tatzberg 41, 01307, Dresden, Germany; Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China.
Researchers discovered new drug binders for tumor necrosis factor-alpha (TNF-α) using iterative library design, array synthesis, and screening. This method yielded potent inhibitors and activators, highlighting novel engineering possibilities for drug discovery.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Biotechnology
Background:
- Identifying novel chemical structures for protein targets is crucial in drug discovery.
- Current high-throughput screening methods are limited by existing chemical libraries, restricting molecular diversity exploration.
Purpose of the Study:
- To discover novel binders for the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α).
- To explore the potential of high-throughput array synthesis and growth algorithms in identifying new chemical entities.
Main Methods:
- Employed iterative Library design - Array synthesis - Screening (i-LAS) technology.
- Utilized a growth algorithm to guide library design for TNF-α binders.
- Synthesized and screened compound libraries against TNF-α.
Main Results:
- Identified compound T17 with a dissociation constant (kd) of 14.8 μM, which protected L929 cells from TNF-α-induced cytotoxicity.
- Engineered T17 into oligomers achieving low nanomolar (nM) affinity binders.
- Demonstrated the ability to switch high-affinity oligomers between inhibiting and activating TNF-α activity by tuning multivalent interactions.
Conclusions:
- The i-LAS technology enables the discovery of novel chemical structures for challenging protein targets.
- Engineered oligomers exhibit tunable activity (inhibitor/activator) against TNF-α, suggesting an oligomerization-induced receptor activation mechanism.
- This approach facilitates the development of molecules with unique properties for therapeutic applications.
