Targeting Disease

Small-molecule natural products target essential proteins rather than those involved in disease, according to a new study (J. Am. Chem. Soc., DOI: 10.1021/ja102798t). Stuart L. Schreiber of the Broad Institute of Harvard and MIT says his team’s findings suggest that drug designers hoping to hit disease proteins will have to look beyond nature for inspiration.

Using network analysis, Schreiber, Paul A. Clemons, and coworkers show that natural products bind to proteins that interact with many other proteins, a hallmark of gene products encoded by essential genes. In contrast, proteins encoded by disease genes tend to have fewer interactions. In addition, the researchers find, approved synthetic drugs tend to strike proteins with network connectivity that more closely resembles that of disease proteins than that of natural-product targets.

“Clearly, natural products can become drugs because many of them are drugs,” Schreiber says. But his team set out to determine whether natural products are optimal compounds for targeting disease proteins. “Our data suggest they are not,” he says. “This is a great challenge for synthetic organic chemistry: How do we turn our attention to new classes of compounds that target disease gene products?”

The fact that natural products aim at proteins encoded by essential genes is not surprising, Schreiber says. Many of them evolved as weapons in microbial warfare, he explains, and “they will target the most essential genes possible.”

“The idea that natural products might be less suited as drugs for human diseases due to evolutionary direction toward highly connected and essential biological processes is significant,” says John A. Porco Jr. of Boston University. “Such fundamental observations are an excellent step toward understanding how we should consider development of new drugs for human disease.”

“Alas, as would have been expected from professor Schreiber and from the Broad Institute, the paper makes a strong case for the idea that the diversity required for pharma-level success is not likely to be provided by strictly small-molecule natural products,” says Samuel J. Danishefsky of Columbia University. But the “paper admirably serves to refocus reader interest on small-molecule natural products as well as synthesis. That’s all to the good.”