October 15, 2012 (Vol. 32, No. 18)

German Company Banking On Natural Products Being Good Blueprints for Drugs

“Natural products have always played a role in drug discovery,” says Dietmar Wolf, Ph.D., executive vp of AnalytiCon Discovery. In fact, about half of all small molecule drugs on the market are derived from natural products or their synthetic analogs. This track record “makes natural products good blueprints for drugs,” says Dr. Wolf, who heads the company’s new U.S. office in Rockville, MD.

When the founders of AnalytiCon Discovery started the company in 2000, they took a novel route to exploring natural products. Traditionally, natural products research relied on bioassay-guided fractionation. In other words, a plant was collected, its metabolites were extracted and tested for a specific biological activity, and then the bioactive component was identified. “This is a time-consuming process,” says Dr. Wolf, and “the active ingredient often turned out to be a well-known compound, making it less attractive for further development.”

Instead, AnalytiCon Discovery takes advantage of chemical diversity by isolating each individual natural compound from plants and microbial strains. Then it identifies the biological activity of single compounds in multiple assays with their clients. This approach is similar to high-throughput screening of synthetic compounds. The company selects the most promising extracts based on a chemical fingerprint and transforms them into pure natural compounds. “We produce about a thousand purified natural compounds products a year,” says Dr. Wolf.

Natural products have fascinating structural and biological properties and are a largely unexplored resource for pharmaceutical, nutraceutical, and cosmetic companies. Small molecules isolated from natural sources, in particular edible plants, are more likely to be accepted by consumers and regulatory agencies than conventional synthetic ones. Because edible plants are generally safe, there’s a greater chance of getting a natural product on the GRAS list, according to Dr. Wolf. As consumer demand for natural products increases, companies are finding them more appealing.

AnalytiCon researchers were part of a recent collaboration with colleagues at the Max Planck Institute for Molecular Genetics. They isolated powerful new natural anti-diabetics, called amorfrutins, from the edible roots of licorice, Glycyrrhiza foetida, and the legume, Amorpha fruticosa. The amorfrutins were discovered by screening AnalytiCon’s library containing thousands of pure compounds derived from edible biomaterials.

The amorfrutins bind to and activate PPARγ (peroxisome proliferators-activated receptor gamma), a regulator of lipid and glucose metabolism. Obese and diabetic mice treated with the amorfrutins showed dramatic improvements in insulin resistance and other metabolic parameters, according to Dr. Wolf. Moreover, he reports, the amorfrutins did not produce the unwanted side effects of weight gain and hepatotoxicity that plague current synthetic PPARγ drugs like rosiglitazone (Avandia). The results were reported in the Proceedings of the National Academy of Science.

AnalytiCon’s LC/MS department supports the medicinal chemistry group by analyzing synthesized compounds generated during hit validation and hit-to-lead optimization phases.

The amorfrutins are an example of promising natural compounds stored in AnalytiCon’s MEGx library and semi-synthetic compounds in the NATx library. These libraries are continuously expanded and include more than 28,000 compounds based on 2,000 chemotypes. The structures of all compounds are completely resolved, and they are ready to be screened.

The MEGx library comprises 1,200 natural products purified from microbial strains (terrestrial and marine sources) and 3,600 natural products purified from plants. Among the microbial products, 70% are novel, as are 40% of plant products. The identity of each natural product is confirmed by LC/MS and NMR. The collection contains highly diverse small molecules, many of which have not been previously published. A proprietary fermentation, profiling, isolation, and structure elucidation process (MEGAbolite®) insures a reliable supply of a natural product for scale up.

The NATx library contains 23,000 compounds with unique three-dimensional chiral scaffolds and decorated pharmacophore functionalities. They combine the advantages of highly evolved natural products with parallel chemistry for efficient drug discovery, such as hit-to-lead optimization. Unique 3D fragments with established chemistry are also available for fragment-based drug discovery.

AnalytiCon Discovery also has a huge collection of plants and microbial strains in storage. “We’re always looking for new biomaterials, and we continuously enhance our collection,” says Dr. Wolf. Biomaterials are collected worldwide under contracts with local governments and authorized organizations, and rules governing biodiversity are always respected.

AnalytiCon’s staff includes natural product and medicinal chemists, biochemists, biologists, and pharmacologists who support clients to develop active ingredients and products. Customers include no less than 75 international companies working in the pharmaceutical, food, and cosmetics industries.

Customers can benefit from a variety of related services, such as structural elucidation, biological screening, assay development, biochemistry support services, and total synthesis of natural products. Assay development routinely involves optimization and validation of critical pathways that drive med-chem programs and lead decisions. Biochemical expertise covers the isolation, characterization, and identification of native proteins from mammalian cells, tissues, and organs for target/biomarker discovery.

For lead generation, the company offers target-to-lead drug discovery modules based on tailored biology and pharmacology building blocks. Clients can select, modify, and align these tools in individual ways.

AnalytiCon’s collection of more than 22,000 microbial strains is the basis for its chemically diverse pure natural compound library.

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