Why going back to the roots of medicine in nature could help fill the drug discovery gap

While humans evolved over a period of approximately 6 million years, breakthroughs in modern medicine as we know it today did not begin until the 19th and 20th centuries. So how did humans manage to survive millions of years of disease without modern drugs and treatments?

This is a question I asked myself when the COVID-19 pandemic hit my family in India in April 2020, when access to vaccines and treatment was very limited. All my years of working as a biomedical scientist, requiring empirical evidence and formal safety testing before using any treatment, took a back seat as I researched potential therapies from every source I could. find, whether scientific articles or folklore. I was ready to try any experimental or traditional medicine that might have a chance of helping my father.

Fortunately, my father recovered. I can’t say for sure if any of the traditional medicines we used actually helped him recover. But as someone whose entire scientific career has been focused on discovering new drugs from chemical compounds found in nature, I wondered if there was a molecule in the traditional drugs we used that might be isolated and optimized to treat COVID-19.

Scientists like me have searched for new drugs for various diseases by purifying compounds that exist in nature instead of synthesizing new ones in the lab. From COVID-19 to antibiotic resistance, I believe past successes and emerging technologies point to the enormous potential for new drug development from natural products.

Early drug development involved the search for plants with medicinal properties. Since then, scientists have been able to isolate the active ingredients that confer medicinal properties on natural products, such as poppy morphine.

The advantage of the natural product

Humans have co-evolved with the rest of nature over time, and obtaining medicine is perhaps one of the most important interactions people continue to have with the natural world. DNA analyzes have shown that early humans may have treated dental abscesses with poplar, which contains the active ingredient aspirin, and Penicillium mold, containing the antibiotic penicillin.

Researchers call molecules like those that give poplar and Penicillium their biological effects natural products because they are produced by living organisms such as microbes, fungi, corals and plants. These natural products have evolved to be structurally “optimized” to perform particular biological functions, primarily to deter predators or gain a survival advantage in a particular environment and over other competitors.

Since natural products are already designed to work in living things, this makes them particularly attractive as a source of drug discovery. While proteins may look different in different organisms, many have similar structural features and functions across species. This may help facilitate the search for related proteins that work in humans.

Natural Products Hall of Fame

Natural products derived from microbes and plants are the greatest resource for drug discovery for modern medicine. For example, the discovery of the antibiotic penicillin in 1940 from Penicillium mold allowed doctors to treat previously deadly infections and started the era of antibiotics.

As of September 2019, more than 50% of FDA-approved drugs currently available are directly or indirectly derived from natural products. One of the best-selling drugs of the past two decades, the cholesterol-lowering drug atorvastatin (Lipitor) is derived from a compound produced by the fungus Penicillium citrinum. From 1992 to 2017, sales of atorvastatin in the United States totaled US$94.67 billion.

Penicillin revolutionized medicine.

Other prominent examples of natural product-derived drugs currently in use today include the antifungal amphotericin B, isolated from soil bacteria. Streptomyces nodosusthe chemotherapeutic taxol, isolated from the bark of the Pacific yew, and the immunosuppressant cyclosporine, isolated from the fungus Tolypocladium inflatum.

I believe that undiscovered treatments for a wide range of diseases lie right under our noses in natural products. In January 2021, the FDA approved voclosporin (Lupkynis), isolated from the fungus Tolypocladium inflatum, to treat lupus. Recently, researchers have looked at cannabidiol and other cannabinoid compounds as a potential way to prevent or treat COVID-19. The FDA has not yet authorized any CBD-containing drugs for COVID-19.

The Challenges of Natural Product Discovery

Researchers are increasingly able to use new technologies and screening methods to isolate previously unidentified natural products. Screening for natural products usually involves browsing through an extensive library of extracts from natural sources. The Natural Product Drug Discovery Core, which I co-founded with my colleague David Sherman at the University of Michigan, for example, searches for potential drug targets in a library of approximately 50,000 natural product extracts each containing 30 to 50 molecules to be tested.

However, drug discovery using natural products is not without its challenges. Since the 1980s, natural products have fallen out of favor due to a number of challenges. These include the difficulty of accessing expensive screening methods and the limitations of technology that is unable to fully analyze the complexity of natural products. There are also ecological and legal considerations, such as sustainable access to samples and maintaining biodiversity. Pharmaceutical companies have scaled back their natural product-based drug discovery programs, and federal funding is also insufficient due to limited profitability.

As antibiotic resistance increases, the development of new drugs and the more responsible use of current drugs becomes even more imperative.

Finding new drugs in nature

New drugs are often needed for unprecedented health emergencies like COVID-19. They are also needed for a health emergency that began long before the pandemic – antibiotic resistance.

A September 2017 report by the World Health Organization reaffirmed that antibiotic resistance is a global health emergency that will seriously undermine advances in modern medicine. If current antibiotics lose their effectiveness, common medical procedures such as cesarean sections and cancer treatments can become extremely risky. Transplantation could become virtually impossible. Antibiotic-resistant microbes were the direct cause of an estimated 1.27 million deaths in 2019. Treating just six of the 18 microbes that pose a threat of antibiotic resistance would cost health care providers more than $4.6 billion a year. United States only. The COVID-19 pandemic has reversed earlier progress in addressing this problem, with antimicrobial resistant infections increasing by 15% from 2019 to 2020. In contrast, antimicrobial resistant infections had fallen by 27% from 2012 to 2017. Among the likely causes of this decline was an increase in antibiotic use, difficulty following infection control guidelines, and longer hospital stays.

According to recent estimates, approximately 75% of approved antibiotics are derived from natural products. There are still thousands of microorganisms in the ocean to explore as potential sources of drug candidates, not to mention all of those on land. In the search for new drugs to combat antibiotic resistance, natural products may still be the way forward.

Ashu Tripathi, Director, Natural Products Discovery Center; Assistant Professor/Research in Medicinal Chemistry, University of Michigan

This article is republished from The Conversation under a Creative Commons license. Read the original article.

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