INVITATION DESIGNS

Scripps Research scientists identify new class of antimalarial compounds

Findings point to the development of novel drugs that could eradicate the disease.

An international team led by scientists from the Genomics Institute of the Novartis Research Foundation (GNF) and The Scripps Research Institute has discovered a family of chemical compounds that could lead to a new generation of antimalarial drugs capable of not only alleviating symptoms but also preventing the deadly disease.

Caption: This is Elizabeth Winzeler, Ph.D. and Stephan Meister, Ph.D. Credit: Photo Scripps Research

In a study published yesterday November 17, 2011, in Science Express, the advance online publication of the journal Science, Elizabeth Winzeler, PhD, a Scripps Research associate professor and member of the GNF, and colleagues demonstrated that the class of compounds was more effective against malaria than some commercially available drugs.

Most antimalarial drugs are only effective during the blood stage, and those that do work in the liver have notable side effects. However, the new class of compounds identified by the team is highly effective against the parasite in both the blood and the liver.

“Because the parasite blood stages are more amenable to high-throughput screening, much research has focused on that area,” said Stephan Meister, PhD, a research associate in the Winzeler lab and first author of the new paper. “We’re excited to have found a class of compounds that appears to target a novel gene and is highly active against the liver stage parasites in mice. This compound class provided us with a lead for the development of novel anti-malaria drugs.”

A Complicated Lifecycle

Despite long-standing efforts to control malaria globally, the disease remains endemic in many parts of the world. According to the World Health Organization, malaria affected about 225 million people in 2009, and killed nearly 800,000. The disease, which tends to strike the poorest and most vulnerable populations in Asia, Africa, and the Americas, is caused by Plasmodium parasites transmitted through the bites of infected mosquitoes.

The Plasmodium parasite has a complicated lifecycle in two hosts—mosquitoes and humans (or other vertebrate). When a malaria-infected mosquito feeds on a person, the parasite enters the human body. Within 30 minutes, the parasite has infected liver cells, where it develops for about eight days without causing noticeable symptoms. In some cases it can even go into hiding in the liver and persist for several months to years.

When this period is over, however, the parasite (now in a different form) leaves the liver and enters red blood cells, where it grows and multiplies. When the infected red blood cells eventually burst, the parasite and Plasmodium toxins are released into the bloodstream, and the person feels sick. Symptoms include fever, chills, headache, and other flulike symptoms; in severe cases, patients can experience convulsions, coma, and liver and kidney failure, which can be fatal.

If a mosquito bites the infected person at this point, the parasite will enter the mosquito, where it will continue the cycle by maturing into a form that can infect the next human host.

Mining the Data

To find compounds to act against the parasite in more than one stage of its lifecycle, the team screened thousands of candidates that were already known to act against malaria parasites in the blood. Only 15 percent looked as if they might also work in the liver—a strong indication, Winzeler said, that “a lot of compounds that are active against blood stages probably aren’t going to do anything about eliminating malaria.”

The group then identified the strongest candidates for drug development by mining the data for groups of related compounds that all showed activity in the liver. In the end, they settled on a cluster related to the chemical imidazolopiperazine. “When we analyzed all of the data, we saw that multiple members of this imidazolopiperazine family were active in blood and liver stages,” Winzeler said.

The imidazolopiperazine family of compounds was especially attractive because it was chemically unrelated to existing antimalarial drugs, and therefore less likely to run into problems with existing resistance. “I wouldn’t want to base a multimillion dollar clinical trial on compounds for which there may be pre-existing resistance,” said Winzeler. “Ultimately, we want to have something that will still be effective in 10 years.”

The group used an automated system of their own design to see how these new compounds fared against malaria parasites incubated in liver cells in the lab. An imaging apparatus took multiple images of each collection of cells over time, and a computer script analyzed those images to see how well the various compounds inhibited the growth of the parasites.

In the end, the team was able to develop compounds that could be taken orally and would stay in the blood long enough to be a viable candidate for drug development. When it was given to mice, the compound provided complete protection against the parasite in the liver, and worked better in the blood than some commercially available drugs.

Spurring Drug Discovery

To better understand how the compound works, the team exposed successive generations of infected mosquitoes to low levels of the compound to produce resistant strains of parasites. They then sequenced the parasites’ whole genomes and looked for genetic changes. “Every [resistant] strain we looked at had a mutation in the same gene,” she said.

By offering a target for other new antimalarial drugs that can act in both the liver and the blood, that gene will provide other researchers fresh ammunition in the fight to eradicate the disease. So, too, will the decision by the team to make all of their data available online.

“We have been making all of our data available to the community to spur drug development,” Winzeler said. “The data on all of the compounds that were tested will eventually be released, and this will allow people at universities and research institutes around the world to mine this data, and to use it to guide their own drug discovery efforts.”

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In addition to Winzeler and Meister, the authors of the Science paper, titled “Exploring Plasmodium Hepatic Stages to Find Next Generation Antimalarial Drugs,” include Selina E Bopp, A. Taylor Bright, and Neekesh V. Dharia, of Scripps Research; David M Plouffe, Kelli L Kuhen, Ghislain MC Bonamy, and S.Whitney Barnes, of the Genomics Institute of the Novartis Research Foundation; and researchers at Columbia University Medical Center, UC San Diego, the Novartis Institute for Tropical Diseases and the Swiss Tropical and Public Health Institute.

Support for the study came from the Wellcome Trust, the Medicines for Malaria Venture, the Genomics Institute of the Novartis Research Foundation, the Swiss Tropical and Public Health Institute, and the Novartis Institute for Tropical Diseases.

Chew gum, lose weight

“Syracuse University scientist uses vitamin B12 to orally deliver appetite-suppressing hormone” 

Most people understand that serious weight loss requires changing attitudes toward what they eat and how often they exercise. But, what if the process could be aided by simply chewing a stick of gum after meals? That’s the question a team of scientists, led by Syracuse University chemist Robert Doyle, is trying to answer. In a groundbreaking new study, Doyle’s team demonstrated, for the first time, that a critical hormone that helps people feel “full” after eating can be delivered into the bloodstream orally.

Doyle’s study was published online Nov. 4, 2011 in the American Chemical Society’s Journal of Medicinal Chemistry and is forthcoming in print. Doyle is an associate professor in the Department of Chemistry in SU’s College of Arts and Sciences. He collaborated on the study with researchers from Murdoch University in Australia.

The hormone, called human PYY, is part of a chemical system that regulates appetite and energy. When people eat or exercise, PYY is released into the bloodstream. The amount of PYY that is released increases with the number of calories that are consumed. Past studies have shown that people who are obese have lower concentrations of PYY in their bloodstream both when fasting and after eating than their non-obese counterparts. Additionally, intravenous infusion of PYY into a volunteer group of obese and non-obese individuals increased the serum levels of the hormone and lowered the number of calories both groups consumed.

“PYY is an appetite-suppressing hormone,” Doyle says. “But, when taken orally, the hormone is destroyed in the stomach and that which isn’t destroyed has difficulty crossing into the bloodstream through the intestines.”

What’s needed is a way to disguise the PYY so that it can travel through the digestive system relatively unharmed. Several years ago, Doyle developed a way to use vitamin B12 as a vehicle for the oral delivery of the hormone insulin. B12 is able to pass through the digestive system with relative ease and carry with it insulin, or other substances, into the bloodstream.

Similarly, his research team attached the PYY hormone to his patent-pending vitamin B12 system. “Phase one of this study was to show that we could deliver a clinically relevant amount of PYY into the bloodstream,” Doyle says. “We did that, and we are very excited by the results.”

The next step involves finding ways to insert the B12-PYY system into such things as chewing gum or an oral tablet to create a nutritional supplement to assist individuals in losing weight in much the same way as nicotine-laced gum is used to help people stop smoking. “If we are successful, PYY-laced gum would be a natural way to help people lose weight,” he says. “They could eat a balanced meal, then chew a stick of gum. The PYY supplement would begin to kick in about three to four hours later, decreasing their appetite as they approach their next meal.”

Research sheds new light on body parts’ sensitivity to environmental changes

Research by a team of Michigan State University scientists has shed new light on why some body parts are more sensitive to environmental change than others, work that could someday lead to better ways of treating a variety of diseases, including Type-2 diabetes.

MSU assistant zoology professor Alexander Shingleton used fruit flies as a model for his research into why some body parts are more sensitive to environmental changes than others. Fruit flies use the same genes to control this process as humans do. Photo by G.L. Kohuth.

The research, led by assistant zoology professor Alexander Shingleton, is detailed in the recent issue of the Proceedings of the Library of Science Genetics.

In particular, Shingleton is studying the genetics of fruit flies and zeroing in on why some of the insects’ body parts will grow to full size even when suffering from malnutrition, while others will not. He uses fruit flies because they use the same genes to control this process as humans.

“The developmental mechanisms by which these changes in body proportion are regulated are really unknown,” Shingleton said.

Shingleton said that in humans, a person’s brain will grow to near full size despite malnutrition or other environmental, or nongenetic, problems.

If scientists can figure out why some organs or body parts are either overly sensitive or insensitive to environmental factors, then it’s possible that therapies could be developed to deal with any number of maladies.

“If we know how we can control sensitivity to environmental issues such as malnutrition, we can, in principle, manipulate genes that are regulating that sensitivity,” Shingleton said. “Genes can be activated so they can actually restore sensitivity.”

Type-2 diabetes is a good example of the body’s insensitivity to nongenetic issues. The most common form of diabetes, Type-2, occurs when the body becomes insensitive to insulin, which is released in response to blood sugar levels. The body needs insulin to be able to use glucose for energy.

“In diabetes, that response is suppressed,” Shingleton said. “We get desensitization. We know people become insulin resistant, but we’re not quite sure why.”

What Shingleton and colleagues discovered is that even when malnourished, the genitals of a male fruit fly continue to grow to normal size.

“The same developmental mechanism that a fly uses to make its genitals insensitive to changes in nutrition may be the same that we as humans use to modulate the responsiveness of individual body parts to changes in nutrition,” he said. “Our job is to try to understand why some body parts are responsive to changes in nutrition and others aren’t.”

Using the fruit fly for this type of research “gives us enormous information about how we as humans work and how we respond to our environment,” Shingleton said. “This provides information on biomedical issues that arise from things like malnutrition or insulin resistance.”

Shingleton’s research is funded by the National Science Foundation and MSU’s Bio/computational and Evolution in Action Consortium, or BEACON.

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