Natural Product Synthesis in the 21st Century: Beyond the Mountain Top
Inventors & their inventions
Axial: https://linktr.ee/axialxyz
Axial partners with great founders and inventors. We invest in early-stage life sciences companies such as Appia Bio, Seranova Bio, Delix Therapeutics, Simcha Therapeutics, among others often when they are no more than an idea. We are fanatical about helping the rare inventor who is compelled to build their own enduring business. If you or someone you know has a great idea or company in life sciences, Axial would be excited to get to know you and possibly invest in your vision and company. We are excited to be in business with you — email us at info@axialvc.com
The review provides a broad perspective on natural product total synthesis and where the field may be headed in the future by Professor Ryan Shenvi. The introductory sections establish some key concepts and terminology around chemical synthesis and natural products. Chemical synthesis joins molecules together through chemical reactions, while degradation breaks them apart. Biosynthesis occurs within cells, self-assembly relies on weak interactions. Shenvi defines natural products as small molecule secondary metabolites produced by organisms, often as "chemical weapons" to impact other organisms. Their properties are refined by natural selection to allow absorption, distribution, and target binding in living systems.
A key point is that natural products and drugs share many properties, since both are designed to modulate biomolecules and physiology. However, drugs represent a compromise between the complexity of natural products and the accessibility/modularity of commercial building blocks for rapid optimization. The author argues that recognition of the advantages of natural product chemical space provides an opportunity for synthesis to regain momentum, if the community commits to exploring function beyond mere synthesis of targets.
After reviewing different orientations of synthesis (target, diversity, etc), the author delves into molecular complexity. Complexity is quantified by properties like ring fusions, stereocenters, and sp3 content. On average, approved drugs tend to be less complex than natural products. The divide has begun to shrink, as drugs are becoming larger and more complex to improve IP coverage, binding affinity/specificity, and suitability for chronic diseases. This convergence bodes well for synthesis, as new tools and strategies will be needed to solve these problems.
A pivotal perspective from Shenvi is viewing synthesis targets dynamically rather than statically. That is, modest changes can be made to natural products to ease synthesis while retaining advantages of the natural scaffold. This allows focus on enabling approaches versus arbitrary acquisition of a fixed target. The author notes cultural issues in publishing that require total syntheses to establish significance, limiting reports on enabling approaches toward useful scaffolds. Broad recognition that local chemical space can exceed the natural product could help reorient focus toward synthetic innovation versus target milestones.
The next sections overview how prediction, accessibility, and automation could transform synthesis. If binding models improve sufficiently to predict affinity given a ligand and protein structure, synthesis could rapidly explore local SAR. Advancing proteome-wide assays allow direct annotation of synthesized compounds. As these tools improve in accuracy and accessibility, synthesis can advance beyond isolated targets into underexplored regions of complex chemical space.
The author notes bottlenecks around target availability from isolation and chemical synthesis. He argues that AI-guided synthesis also relies heavily on diverse human-generated data. More studies on complex scaffolds and analogs are vital to build predictive models and synthesis tools. If prediction and validation grow more powerful, automation could accelerate exploration beyond natural products. However, success depends on addressing gaps in data.
This review compellingly recasts natural product synthesis as a means of opening passages into therapeutically useful chemical space, rather than conquering arbitrary targets. He argues that the future is bright if the community fosters growth at the interface of synthesis and biology. Modest modification of natural product structures guided by prediction and annotated by assay could transform the speed and significance of synthesis. The unglamorous work of trailblazing could lead the field in creative new directions beyond mountains whose summits represent an outdated definition of success.
In summary, this perspective article makes a thoughtful case for how natural product synthesis can evolve by embracing enabling methodologies, computational modeling, biological annotation, and flexibility in target definition. If pursued vigorously, these approaches could reinvigorate the fundamental science of organic synthesis and its translation toward therapeutic goals. The author challenges conventional assumptions in a nuanced way and lays out opportunities for the field to grow in significance and impact. By linking synthesis, prediction, assay, and automation, while focusing on deep exploration of complex chemical space, natural product synthesis may enjoy a bright future at the nexus of chemistry and biology.
https://pubs.acs.org/doi/10.1021/acscentsci.3c01518
