An Invitation to Natural Product Science for Drug Discovery

Have you ever heard the term "natural product"? The Japanese word for natural, 天然 (tennen), is defined as "being in a state untouched by human hands." The character 天 (ten), meaning heaven, evokes a sense of "something created by the gods." A "natural product" (天然物, ten-nen-butsu) is defined as "a substance produced by a living organism"—in essence, a substance made by an organism, just as the gods intended. Natural products are compounds produced by plants, microorganisms, and marine life, and they have long been the source of many important medicines. Microorganisms such as actinomycetes and fungi, in particular, have provided a wealth of brilliant natural products, from the early antibiotic streptomycin to avermectin, the basis for a recent Nobel Prize-winning antiparasitic drug (Figure 1).

However, it has become clear that microorganisms possess "silent genes" that lie dormant, holding the potential to produce even more amazing compounds. So, how can we awaken these sleeping genes? We focused on interspecies biological interactions and developed a "co-culture method" where microorganisms and animal cells are cultured together. We hypothesized that when a pathogenic microorganism invades an animal's body, it will be attacked by immune cells. This stress might cause the microorganism to activate its dormant silent genes and produce some kind of compound in an attempt to survive (Figure 2).

In fact, we have succeeded in producing new compounds by co-culturing pathogenic actinomycetes, pathogenic fungi, and even Koji mold and gut bacteria with animal cells.

Now, do these compounds possess the kind of biological activity that could make them into drugs? We focused on human proteins responsible for biological activity and developed the "target protein-oriented natural product isolation method," which uses a protein "fishing rod" to "catch" active natural products (Figure 3).

Using this method, we have "caught" many natural products, including compounds with anti-cancer activity and others that cause neural stem cells to differentiate into neurons. These compounds have become new anti-cancer drugs and seed compounds for neurodegenerative diseases (Figure 4).

Thus, by using "silent gene activation" and the "protein fishing rod," we can discover even more "natural products" that will be useful to humanity! Wouldn't you like to join us in searching for such treasures for humankind? And wouldn't you like to take a peek at how these natural products work inside our cells?