COVER STORY
ESSENTIAL INGREDIENT A large natural product collection, including microbial cultures in fermentation flasks, is integrated into Albany Molecular Research's drug discovery program.
REDISCOVERING NATURAL PRODUCTS Cast aside for years, natural products drug discovery appears to be reclaiming attention and on the verge of a comeback A. MAUREEN ROUHI, C&EN WASHINGTON
T
HE PHARMACEUTICAL INDUSTRY'S PRODUCTIVITY
continues to be dismal. This state of affairs is due to many factors, and one may have been the diminished interest in natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry
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However, the tide may be turning, for three reasons. First, combinatorial chemistry's promise to fill drug development pipelines with de novo synthetic small-molecule drug candidates is unfulfilled. Second, the practical difficulties of natural products drug discovery are being overcome by advances in separation technologies and in the speed and sensitivity of structure elucidation. And third, a compelling case is being made for the intrinsic utility C&EN / OCTOBER
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COVER STORY SUPERiMPOSABLE Catalytic domains of leukotriene A4 hydrolase (blue), thermolysin (yellow), and angiotensinconverting enzyme (red) are similar even though they catalyze different reactions.
thetic compounds with natiiral-prcduct-derived pharmacophores (5%), and synthetic com"* pounds designed on the basis of knowledge gained from a natural product (that is, a natural product mimic; 23%). In certain therapeutic arJr eas, the productivity is higher: 78% of antibacterials and COURTESY OF HERBERT WALDMANN 74% of anticancer compounds are of natural products as natural products or have been derived sources of drug leads. from, or inspired by, a natural prodFor decades, natural uct. These numbers are not surprising products have been a if it is assumed that natural products wellspring of drugs and evolved for self-defense. But the indrugleads. According to arecent surfluence of natural products is signifvey by David J. Newman, Gordon M. icant even in therapeutic areas for Cragg, and Kenneth M. Snader of the Na- which they might not seem relevant, such tional Cancer Institute, 61% of the 877 as cholesterol management, diabetes, arthrismall-molecule new chemical entities in- tis, and depression. troduced as drugs worldwide during "Imagine ifwe eliminated natural prod1981-2002 can be traced to or were inspired ucts from drug discovery in the past," sugby natural products \Jf. Nat. Prod., 66,1022gests Barry A. Berkowitz, a corporate vice (2003)}. These include natural products president at Albany Molecular Research. (6%), natural product derivatives (27%), syn- "We would not have the top-selling drug
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class today, the statins; the whole field of angiotensin antagonists and angiotensinconverting-enzyme inhibitors; the whole area of immunosuppressives; nor most of the anticancer and antibacterial drugs. Imagine all of those drugs not being available to physicians or patients today" Despite that record of productivity natural products drug discovery was de-emphasized in many big pharmaceutical companies in recent years. Newman says the trend began in the early 1990s, and the reasons were primarily practical. When automation, robotics, and personal computers came onto the drug discovery scene around the mid-1980s, chemistry became the ratelimiting step in drug discovery programs, he explains. The situation worsened in the early 1990s, with high-throughput screening, fast personal computers, and the breakneck pace at which molecular biology was identifying biological targets. Chemists couldn't supply the huge numbers of compounds required by screens that by this time were taking months instead ofyears. At the same time, natural products drug discoverywas still being done the traditional way: Drug targets were exposed to crude
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COVER STORY
SPEAKING
OUT
The Case For Natural Products Research
N
atural products research is almost disappearing. The field is perceived as old-fashioned and unexciting: Here's another structure from an obscure organism—so what? The most interesting compounds already have been found, many people believe. If the chances for novel discovery are slim, why bother? In addition, sampling natural products outside one's national boundaries has become torturous. Against this background, C&EN spoke with Jerrold Meinwald, Goldwin Smith Professor of Chemistry at Cornell University and a pioneer in the field of chemical ecology, about the outlook for natural products research.
C&EN: Have most of the interesting things been discovered? Meinwald: By no means. For flowering plants, about 250,000 species have been described, of which perhaps 10% have been examined chemically. Many were examined decades ago, when techniques were relatively crude. We can do a more thorough job and find many more interesting compounds if we pick target plants that are interesting for some reason and study them in chemical depth. The number of insect species described is about 1 million, and many more have never been described. Most of these insects comMeinwald municate or defend themselves through chemistry, and maybe only a few thousand species have been examined. As chemists, we've barely begun studying insects. Soil bacteria have been extremely important sources of antibiotics, and we certainly need new antibiotics very badly. However, only a very small percentage of soil bacteria have ever been cultured. That most of them are unculturable means that we must be missing a huge number of metabolites. Researchers are getting around this issue by getting DNA directly out of the soil, putting it into host organisms, and examining the metabolites expressed. Most marine organisms probably have not yet been described. And most of those
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already described have not been examined chemically. Natural products from marine invertebrates often have structures unlike those of compounds from terrestrial organisms. A whole new chemical vocabulary from the marine environment has yet to be learned. We are far from understanding what these compounds do for the organisms that produce them, or what they might do for us. C&EN: If so much can be exEAT M E NOT Brightly colored insects keep amined, where should one away predators with distasteful or toxic begin? compounds. Meinwald: Doing it randomly is not intellectually satisfying. It could offer valuable guidance about where would be nice to have a biorational way to to start. Good field biologists are likely to select organisms for study, and there are notice interactions that might provide several possible guidelines. clues to interesting chemistry. Let's look at "living fossils," organisms that are the sole representative of their C&EN: How are the intellectual type, the ginkgo tree, for example. Ginkgos are an ancient species. Their relatives property issues arising from natural are long since gone. Perproducts drug discovery to be haps some wonderful addressed? chemistry has preserved Meinwald: The problem of who "owns" the ginkgo when all its relnature merits many hours of discussion. atives became extinct. Right now, the concept of biopiracy is defeating many attempts to discover and deGinkgo trees have in fact velop new natural products for human been the source of interbenefit. The sad thing is that the problem esting natural products. creates conflicts even among different The ginkgolides being groups within the same country. studied by [Columbia University professor] Koji In Brazil, for example, one group of inNakanishi are now coming digenous Amazonian people who felt they to the fore as memory aids. had not been fairly represented terminatIn a field that has been ed an agreement with researchers from ravaged by herbivores, some plants, althe University of Sao Paolo on a project to though they are without protective strucstudy medicinal compounds coming from tures, are untouched. Perhaps they are their region. Nobody benefits from this distasteful or toxic and are therefore probehavior. If potential new medicines are tected against natural enemies. Very well not discovered, developed, produced, and preserved plants are likely going to be sold, no one profits. In the meantime, chemically interesting. mindless logging continues and habitats are lost. When the species producing poLook at insects. Many species use camtentially useful compounds are conseouflage to evade predators, but some, quently lost, they're gone forever. For the such as ladybugs, call attention to themBrazilians, or anyone else, to fight among selves with brightly colored markings. themselves in this way is heartbreaking. Why? Perhaps to remind a bird that it But why look to Brazil? You can took for vomited the last time it ate one of them. chemical treasures in your backyard. Brightly colored insects tend to have sysWhile it is true that the greatest species temic poisons or defensive sprays, and diversity is found in tropical rain forests, they advertise it. there is still plenty to be discovered at Other biorational ideas are possible. home. Chemists need to talk to biologists, who
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C&EN: How has support for natural products research changed in the past 10 to 15 years? Meinwald: The old-fashioned ap proach—collect, isolate, elucidate—will not excite anybody and won't get funded. Organic chemists who want to work in this area need to make convincing argu ments why what they want to do is terrif ically important and interesting. As one small example, we're starting a new effort to look at spider venoms. Spiders have been examined before, but of the 40,000 described species not more than a few hundred have been studied and most of them not thoroughly. Very little is known about the chemistry of spi der venoms. What we know for sure is that all spiders earn their living by para lyzing their prey. And the neurochemical agents responsible for this activity are right in the venom. Nowadays, when you can do chemistry on a very small scale, a dozen spiders may be enough to find a novel neuropharmacological agent or to define a novel drug target.
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C&EN: How else can natural prod ucts research be more appealing? Meinwald: It's shortsighted in a way to study nature's chemistry only from the point of view of, "Can I make a drug out of it?" For some researchers, it is even more interesting to look at natural prod ucts from the point of view of their signif icance to the producing organisms. It is intellectually rewarding to try to understand how these organisms are talking to each other, what they are say ing, what chemicals they use to do so, how they get those chemicals, and how chemical communication systems evolved. That is basic knowledge. But the more you understand the chemistry of biotic interactions, the better you could manage forests, pursue agriculture, and avoid parasitic diseases and disease vec tors and the better you could foresee the consequences of introducing new species or eradicating others. Extraorganismal interactions make up a chemical web that keeps the environ ment working the way it does. With the techniques now available, chemical ecol ogy—which is the study of the chemical interactions between organisms—is poised to look at nature in a new way. To understand biotic interactions at a molec ular level is both a great opportunity and a major challenge for future chemists.
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COVER STORY extracts, and in case of a hit—that is, evidence of activity—the extract was fractionated and the active compound isolated and identified. The process was slow, inefficient, and labor intensive, and it did not guarantee that a lead from screening would be chemically workable or even patentable. In addition, natural products can get companies entangled in sticky intellectual property issues, according to Cornell University professor Jerrold Meinwald. Negotiating agreements that are fair to all concerned parties to develop natural products collected in foreign countries has become "extremely difficult," he says. Meanwhile, by the early 1990s, combinatorial chemistry was creating a buzz. It wasn't only faster and cheaper than natural products drug discovery, it also had the great advantage of clarity with respect to intellectual property Drug companies paid attention.
At Pfizer, for example, the number of compounds advancing from hits to leads from the screening of combinatorial libraries was much higher than from natural products, according to Christopher A. Lipinski, an adjunct senior research fellow at Pfizer Global R&D and author of the renowned rules for designing compounds with druglike properties. On this basis, natural products lost the competition for resources. "It was a no-brainer," he says. But when productivity is measured by de novo synthetic small molecules advancing from hit to lead to approved drug, combinatorial chemistry offers zilch. For the period 1981-2002, "we have not been able to identify a de novo combinatorial compound approved as a drug in this time frame," Newman and coworkers write. "However, compounds that have been optimized by combinatorial chemistry are in all phases of drug development. Combi-
"When you have no idea where to begin in a drug discovery program, nature is a good starting point."
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natorial chemistry may not currently be delivering as a discovery tool, but it is excellent for further development of active compounds," Newman adds. "The alarming decline in the number of new chemical entities in the past decade, from an average of 30 or so to as few as 17, has correlated with" decreased interest in natural products drug discovery Berkowitz says. The trend is not surprising in as much as natural products have been proven sources of drugs, he adds. "IN TOO MANY companies, in my view, management went all out to make combinatorial chemistry the way to get new leads, and it did not work because the need for structural complexity was restricted by the requirement for acceptable purity," says Ralph F. Hirschmann, a professor of bioorganic chemistry at the University of Pennsylvania. For 37 years, he worked in various capacities at Merck, and during his tenure as head ofbasic research, Merck developed several blockbuster drugs. Although combinatorial chemistry had not been proven as a drug discovery tool, many companies committed to it as the
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