In nature, biotoxins often pose a deadly threat, but they also hold great promise for patients. Drugs based on snake venom have been used to treat cardiovascular disease; peptides from the venom of the "killer sea snail" have become a painkiller. ...... Now, a toxin from an unassuming sea creature may offer new opportunities for cancer treatment. New opportunities.
In 2013, scientists isolated a class of cyclic imine toxins, named portimine A (PA for short), in a benthic dinoflagellate with the Latin name Vulcanodinium rugosum.
At that time, a variety of cyclic imine toxins had been identified from different marine microorganisms, which on the one hand may be enriched in seafood such as shellfish through the food chain and threaten our health; on the other hand, their potent biological activities also portend the potential for disease treatment. Unfortunately, due to their high neurotoxicity, these cyclic imine toxins are not readily available to us.
PA is an exception. In contrast to other known cyclic imine toxins, PA is highly cytotoxic in the face of a wide range of cancer cells but less toxic overall to individual organisms, and thus has the potential to lead to entirely new cancer therapies. In addition, recent studies have pointed out that PA can selectively induce apoptosis while avoiding necrotic apoptosis as much as possible.
Five years later, scientists isolated another cyclic imine toxin from V. rugosum: portimine B (PB for short). Interestingly, although the two are mutual isomers (the same molecular formula but slightly different structures), PB does not have the same tantalizing anticancer prospects as PA. Thus, the basis for PA-specific cancer cell killing is likely to be hidden in the key structural differences between the two molecules.
However, the mechanism of PA's biological activity remains unknown, an important reason being that one has not yet been able to obtain sufficient quantities of portimine material for analysis. In nature, dinoflagellates biosynthesize very limited amounts of portimine; and in the laboratory, scaleable chemical synthesis is frustrated by the complex structure of portimine, which is difficult to achieve.
In a Nature paper that has just gone online, a team of researchers led by Prof. Phil Baran of the Scripps Research Institute has brought about an important breakthrough. The latest study realizes the scalable synthesis of portimine, and further reveals the structural basis for the anti-cancer activity of PA as well as its mechanism of action, suggesting a potential new target for cancer therapy. Dr. Junchen Tang and Dr. Weichao Li are the co-first authors of the paper.
The first thing the team had to tackle, naturally, was the challenge of portimine synthesis. Inspired by the two-phase strategy for the synthesis of terpenoids, the team developed an innovative synthetic route to accomplish this challenging task. To do so, the authors first constructed the carbon ring in the lowest oxidation state; they then sequentially added functional groups to build the target molecule in the oxidized state. Using this strategy, the team successfully synthesized PA, PB, and other analogs.
This study confirmed that the synthesized PA was highly cytotoxic against multiple species of cancer cell lines and did not kill normal human peripheral blood mononuclear cells with excellent selectivity. In addition, PA was also effective in inhibiting tumor growth in a mouse assay.
Based on the analysis and comparison of the synthetic results, the study clarified the source of PA's toxicity to cancer cells. The authors noted that the hydroxyl stereo configuration at carbon atom 5 (C5) is critical for molecular activity, making PA a unique stereoselective compound. In contrast, PA isomers with the opposite C5 configuration are significantly less cytotoxic.
Therefore, if there are proteins that strongly interact with PA, but not with isoforms of opposite C5 configuration, then such proteins are likely to be target proteins of PA. Based on this line of thinking, the team used proteomics experiments to find the only protein that fit the bill: NMD3. NMD3 is an out-of-nucleus transport protein for the large subunit of ribosomal 60S, and this study was the first to find a small-molecule ligand that specifically targets NMD3.
Subsequent studies have suggested a possible explanation for PA killing cancer cells but not normal cells. the interaction of NMD3 with PA blocks the process of ribosome aggregation to form polysaccharides, thereby inhibiting de novo protein synthesis. As a result, the expression of proteins critical for reproduction and survival (e.g., MYC and MCL-1) is impeded, ultimately leading to apoptosis. Compared to normal cells, the above pathways are particularly active in cancer cells and therefore exhibit selectivity.
For the next research plan, Dr. Weichao Li said that the research team will work on structural optimization on the one hand in order to get better in vivo results; on the other hand, they will explore which STAGE of ribosomal 60S large subunit is affected by PA, so as to parse out this particular mechanism in detail. In addition, the team speculates that portimine may be a molecular glue or capable of possible PROTAC modification, so future research will continue to explore the possibility of portimine as a potential cancer drug as well as protein degradation therapy.
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