Natural Product Drug Discovery and the Challenge of Target Identification
Natural products continue to provide a valuable source of novel bioactive compounds. However, their structural complexity and potential for multi-target engagement have often made target identification and mechanism-of-action studies difficult.
Recent Applications of CETSA in Natural Products
A recent comprehensive review highlights several examples of how CETSA® has clarified mechanisms of clinically relevant natural products:
- CETSA identified purine nucleoside phosphorylase (PfPNP) as a primary target of quinine, explaining how it interferes with purine salvage pathways in Plasmodium falciparum. You can read this case in greater detail in our app note “The Power of Proteome-wide CETSA®”.
- CETSA confirmed that oridonin and curcumol bind nucleolin, providing mechanistic insight into their anticancer effects through inhibition of ribosome biogenesis and induction of apoptosis.
- Thermal proteome profiling (TPP) revealed that staurosporine, a pan-kinase inhibitor, induces stability shifts across over 50 kinases, demonstrating CETSA’s ability to map compound selectivity and off-target interactions.
Advanced CETSA Techniques and Their Impact
Advanced CETSA methods such as mass spectrometry-based CETSA (MS-CETSA) and TPP extend analysis to a proteome-wide scale. These approaches allow simultaneous assessment of thermal stability changes across thousands of proteins, offering detailed insights into how compounds interact with complex biological systems.
Combining CETSA with complementary techniques like DARTS and SPROX provides additional validation of target engagement, supporting confident identification even for natural products with complex or multi-target profiles.
High-Throughput CETSA and Early Drug Discovery
Recent developments in high-throughput CETSA formats, including immunoassays and reporter-based systems, have expanded the assay’s applications into large-scale screening. These methods support:
- Efficient hit validation
- Quantitative assessment of compound binding affinities
- Informed analysis of structure-activity relationships
Such capabilities can significantly improve the speed and precision of early-stage drug discovery programs.
Supporting Drug Discovery with CETSA
The reviewed studies illustrate how CETSA provides reliable data on drug–target interactions in living cells, enabling a clearer understanding of natural products’ mechanisms of action. By identifying both primary and potential off-target interactions, CETSA contributes to more informed decisions in drug development.
At Pelago Bioscience, we are dedicated to applying and advancing CETSA technology to help our partners identify, validate, and optimize drug candidates effectively.
Interested in exploring CETSA for your drug discovery projects?
Contact Pelago Bioscience to learn how we can support your research.
To read the full review, visit this link.
