The discovery, published in Molecular Plant, could transform how scientists investigate a family of natural products associated with pain relief, antimalarial activity, anticancer research and pest control. Although these molecules have attracted scientific interest for nearly two centuries, their intricate structures and unusual chemistry have made them exceptionally difficult to synthesize. One of the best-known examples, aconitine, was isolated almost 200 years ago but remains notoriously challenging to reproduce through conventional laboratory chemistry.

Larkspur, also known as Delphinium because of its dolphin-shaped flowers, and wolfsbane, or monkshood, belong to a group of plants that manufacture diterpenoid alkaloids as chemical defenses. These specialized metabolites are built from carbon-rich diterpenoid frameworks and contain nitrogen, a feature that gives many of them powerful biological activity. The same molecular properties that make the compounds dangerous can also make them valuable starting points for drug discovery, provided researchers can understand their activity and control their production.

“Plants are the best chemists around,” said Björn Hamberger, a study author and the James K. Billman Endowed Professor in Michigan State University’s Department of Biochemistry and Molecular Biology. Over millions of years, plants have evolved enzymes capable of assembling, modifying and reshaping molecules with extraordinary precision. Scientists are increasingly studying these natural pathways not only to understand plant biology, but also to adapt them for sustainable manufacturing of medically important compounds.

The research began with an international collaboration formed after Hamberger encountered scientists from Tomáš Pluskal’s laboratory at the Czech Academy of Sciences during a conference in Barcelona. Both groups were investigating diterpenoid alkaloids, but in different plant species. The Michigan State team was focused on larkspur, while the Czech researchers were examining wolfsbane. Their shared interest allowed them to compare related biochemical systems and search for common molecular mechanisms.

To uncover the pathway, the researchers examined several species of larkspur and wolfsbane and analyzed gene activity in different plant tissues. Their goal was to identify genes that became active at the correct time and place for alkaloid production. This process resembles reconstructing an assembly line from scattered components: if a single enzyme is missing or inactive, the downstream reactions cannot proceed, and the final compound fails to appear.

The team ultimately identified a set of genes encoding six previously uncharacterized enzymes. These enzymes carry out the entry steps required to construct a diterpenoid alkaloid called atisinium. Rather than simply joining small molecules together, the enzymes guide the developing compound through a series of precise structural changes. They help the molecule fold into its complicated three-dimensional configuration and enable the incorporation of a crucial nitrogen source, an unexpected feature that was central to understanding the pathway.

To test whether the genetic blueprint worked, the scientists transferred the selected genes into tobacco plants. The tobacco acted as a living biofactory, using its own cellular machinery to produce the introduced enzymes. Once the engineered plants began making the target chemicals, researchers analyzed their molecular contents and confirmed that the six-enzyme system could successfully generate atisinium. This result provided experimental evidence linking specific genes to the earliest stages of diterpenoid alkaloid biosynthesis.

The achievement does not yet produce a finished medicine, and the compounds remain highly toxic. However, it gives researchers a new route for studying the broader alkaloid family without relying exclusively on wild plants or difficult chemical synthesis. In the future, similar pathways could be transferred into yeast, tobacco or other engineered organisms capable of producing larger and more consistent quantities. Such systems could support toxicity testing, structural modification and the search for therapeutic effects while reducing pressure on rare or slow-growing plant sources.

Garret Miller, a co-first author and former researcher in the Hamberger laboratory who is now an assistant professor of biotechnology at the University of Michigan-Flint, said that understanding how these plants create their compounds could open entirely new routes for testing. Lana Mutabdžija, a graduate student at the Czech Academy of Sciences and co-first author, added that the long-term goal is to develop new drugs inspired by natural products. By revealing how larkspur and wolfsbane build their most potent chemical defenses, the researchers have taken an important step toward turning botanical poisons into programmable sources of future therapeutics.

Subject of Research: Biosynthesis of diterpenoid alkaloids in larkspur and wolfsbane

Article Title: Characterization of the entry steps in diterpenoid alkaloid biosynthesis

Web References: https://www.sciencedirect.com/science/article/pii/S1674205226001905 ; https://doi.org/10.1016/j.molp.2026.05.022

References: Molecular Plant, DOI: 10.1016/j.molp.2026.05.022

Image Credits: Paul Henderson

Keywords: larkspur, wolfsbane, monkshood, diterpenoid alkaloids, plant biochemistry, biosynthesis, atisinium, natural products, biotechnology, drug discovery

At its core, the research presents a detailed analysis of how the flower extract of Dipterocarpus obtusifolius exhibits significant antioxidant properties. Oxidative stress is known to be a contributing factor in the development and progression of various types of cancers. By neutralizing free radicals, antioxidants can potentially halt or even reverse some of the damaging processes that lead to carcinogenesis. The study mentions that the flower extract showcases a rich profile of bioactive components, which may work synergistically to enhance its overall antioxidant activity.

The selective cytotoxic activity of the flower extract stands out as a highlight of this research. Unlike conventional chemotherapeutic agents that often indiscriminately target both cancerous and healthy cells, the compounds extracted from Dipterocarpus obtusifolius appear to selectively induce apoptosis, or programmed cell death, in cancer cells. This attribute is particularly critical for improving treatment efficacy while minimizing side effects, a persistent challenge in the field of oncology.

The methodology employed in this research is robust, featuring a range of analytical techniques to profile the bioactive components of the flower extract. High-performance liquid chromatography (HPLC) was utilized to separate and quantify the various phytochemicals present, while in vitro assays helped determine the cytotoxicity levels against several gastrointestinal cancer cell lines. This meticulous approach ensures that the findings are not only reliable but also replicable for future studies.

A significant portion of the study focuses on the specific types of gastrointestinal cancers targeted by the dipterocarp flower extract. Gastric and colorectal cancers, both of which have alarmingly high incidence rates globally, were highlighted. The researchers posited that the compounds within the flower extract could play a preventive role by inhibiting tumor growth and proliferation in these types of cancers, which are linked to dietary factors and lifestyle choices.

Furthermore, the implications of these findings extend beyond the laboratory setting. Through this research, the authors advocate for further exploration into the potential integration of Dipterocarpus obtusifolius extract into dietary supplements or even as an adjunct therapy in clinical oncology. Such applications could provide patients with additional tools in their battle against cancer, emphasizing the importance of natural products in modern medicine.

As researchers continue to explore the mechanisms underlying the observed selectivity of the extract towards cancer cells, it opens up a pathway for drug development. Identifying the key bioactive compounds responsible for its anti-cancer effects could lead to the synthesis of new, targeted therapies that leverage the principles of nature.

Importantly, the study calls attention to the sustainability and ethics surrounding the harvesting of natural resources like Dipterocarpus obtusifolius. As the demand for natural extracts rises, it is critical to balance the therapeutic benefits with responsible sourcing practices to ensure the conservation of these valuable plants for future generations.

The research also emphasizes the need for robust clinical trials to validate the findings before any widespread application. While the results are promising, transforming plant extracts into clinically viable treatments necessitates rigorous testing to ascertain their safety, efficacy, and best-use scenarios.

As the scientific community digs deeper into the potential of natural products in drug discovery, studies such as this one lay the groundwork for future innovations in cancer treatment. The nexus between traditional herbal medicine and modern scientific inquiry can provide new avenues for tackling complex health challenges.

Ultimately, the contributions of Luechine and collaborators to the understanding of Dipterocarpus obtusifolius flower extract present a vital step forward in the search for safer, more effective cancer therapies. It serves as a reminder of the immense untapped potential lurking in nature, waiting for the day it can significantly alter the trajectory of modern medicine.

The ongoing exploration of bioactive components might soon yield collaborations between ethnobotanists, oncologists, and industrial biochemists dedicated to translating these findings into practical health solutions. As the world grapples with rising cancer diagnoses, this research could lead to holistic treatment strategies that blend the wisdom of traditional knowledge with cutting-edge scientific discoveries.

While there’s still much to learn, studies like these are paving the way for a future where natural remedies complement conventional medicine, ultimately leading to improved patient outcomes and a healthier society.

Subject of Research: The antioxidant and selective cytotoxic activity of Dipterocarpus obtusifolius flower extract against gastrointestinal cancer.

Article Title: Antioxidant and selective cytotoxic activity of Dipterocarpus obtusifolius flower extract against gastrointestinal cancer, with bioactive component profiling.

Article References:

Luechine, A., Techasen, A., Phetcharaburanin, J. et al. Antioxidant and selective cytotoxic activity of Dipterocarpus obtusifolius flower extract against gastrointestinal cancer, with bioactive component profiling. BMC Complement Med Ther (2026). https://doi.org/10.1186/s12906-026-05247-z

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05247-z

Keywords: Antioxidant, Cytotoxic activity, Dipterocarpus obtusifolius, Gastrointestinal cancer, Bioactive compounds.

Lasso peptides are synthesized by bacteria through a fascinating biosynthetic pathway wherein ribosomes assemble linear chains of amino acids, which are subsequently folded into a slipknot-like structure by specialized biosynthetic enzymes. This unique topology bestows lasso peptides with extraordinary stability against enzymatic degradation and environmental stressors. Thousands of different lasso peptides have been identified across microbial species, many exhibiting potent antibacterial, antiviral, and anticancer properties that underscore their therapeutic promise.

Professor Doug Mitchell, co-leader of the study and Director of the Vanderbilt Institute for Chemical Biology, emphasized the untapped potential of these molecules: “The unique structural features of lasso peptides make them ideal candidates for targeting challenging receptors and developing robust oral therapeutics. By creating a dedicated language model tailored for these peptides, we now have a powerful computational tool to accelerate discovery and design in this emerging field.”

While machine learning has become integral in analyzing vast biological datasets, existing AI models such as AlphaFold, despite their revolutionary impact on protein structure prediction, face intrinsic limitations when applied to lasso peptides. The atypical lasso fold deviates significantly from canonical protein structures, rendering traditional prediction algorithms ineffective in accurately modeling their complex topology. This gap motivated the development of LassoESM, a bespoke protein language model specifically trained on the sequences and structural intricacies of lasso peptides.

Unlike generic protein language models that learn from a broad range of protein sequences, LassoESM was meticulously trained on a curated dataset of thousands of experimentally validated lasso peptides. The model uses a masked language modeling technique, wherein fragments of peptide sequences are concealed and predicted, enabling the model to learn the underlying “language” of lasso peptide biosynthesis and folding patterns. This deep understanding allows LassoESM to capture subtle sequence-structure relationships unique to the lasso fold, which conventional models overlook.

A core functionality of LassoESM lies in its ability to predict interactions between lasso peptides and their biosynthetic enzymes, particularly lasso cyclases—the specialized enzymes responsible for catalyzing the knot-tying step of peptide biosynthesis. Since each lasso cyclase recognizes specific peptide substrates much like keys fitting into distinct locks, deciphering these interactions is crucial for engineering novel peptides with designed functionalities. The LassoESM model can infer which lasso cyclase pairs are compatible with a given peptide sequence, a feat that was previously challenging due to sparse experimental data and complex enzyme-substrate specificity.

The collaborative effort harnessed the complementary expertise of the Mitchell and Shukla laboratories, combining bioinformatics, machine learning, and experimental validation. They initially employed bioinformatics approaches to collect a comprehensive catalog of lasso peptides from diverse microorganisms, followed by manual validation to ensure the accuracy of sequence annotations. This high-quality dataset was essential for reliably training the language model. Subsequently, the model was fine-tuned for multiple predictive tasks, including lasso peptide enzymatic compatibility, structural property inference, and functional annotation.

Dr. Diwakar Shukla, co-leader and chemical engineering professor at the University of Illinois Urbana-Champaign, highlighted the transformative impact of this approach: “By decoding the molecular ‘language’ of lasso peptides, LassoESM opens new horizons in predicting properties and functions that have remained elusive. This tool enables us to not only predict structure but also to rationally design peptides with tailored features for specific biomedical applications.”

Despite the limited availability of labeled experimental data—a common bottleneck in peptide research—LassoESM demonstrated robust performance in predicting diverse lasso peptide properties. This capability significantly reduces the empirical trial-and-error burden traditionally associated with discovering and optimizing peptide therapeutics. The model thereby streamlines the development pipeline from sequence to functional candidate, accelerating translational applications in industry and medicine.

Looking ahead, the researchers aspire to extend this AI-driven framework to other classes of peptide natural products beyond lassos. They envision developing specialized language models capable of capturing the nuances of various peptide topologies and their biosynthetic strategies. Additionally, the team aims to leverage LassoESM in engineering peptides that selectively target specific proteins, potentially creating a new generation of peptide-based therapeutics with enhanced efficacy and stability.

The development and application of LassoESM exemplify the power of interdisciplinary collaboration and cutting-edge computational resources. Supported by the National Institutes of Health and facilitated by the robust infrastructure at the Carl R. Woese Institute for Genomic Biology, this research represents a significant advance in peptide engineering. As machine learning continues to evolve, tailored models such as LassoESM are poised to revolutionize how scientists understand, design, and deploy complex biomolecules in real-world therapies.

In summary, LassoESM is an innovative language model that captures the structural and functional essence of lasso peptides, overcoming longstanding challenges in prediction and design. By enabling precise forecasting of peptide properties and enzyme compatibility, it paves the way for rational, AI-driven development of novel therapeutics. This work stands as a compelling testament to the synergy between computational biology and experimental science in transforming drug discovery.

Subject of Research: Lasso peptides and protein language models for biomedical and industrial applications

Article Title: LassoESM a tailored language model for enhanced lasso peptide property prediction

News Publication Date: 29-Sep-2025

Web References:
https://doi.org/10.1038/s41467-025-63412-3

Image Credits: Xuenan Mi, Isaac Mitchell

Keywords: Protein engineering, Machine learning, Artificial intelligence, Peptides, Drug discovery, Bioinformatics