Profiles
Wes Van Voorhis: Taming an Elusive Adversary
Infectious diseases specialist Wes Van Voorhis, Professor, Department of Medicine, Adjunct Professor of Pathobiology, recalls one of the worst malaria cases he ever saw. His patient, a teenage boy, had already been treated for malaria six times when Van Voorhis assumed his care. Each treatment the scientist tried reduced the number of parasites temporarily. Every time, the parasites surged back, causing high fevers, shaking chills, wrenching headaches, nausea and vomiting, and prostration. A cocktail of four drugs finally cured the teenager, but for a long time, success was elusive.
Success continues to elude the worldwide effort to eradicate malaria. The disease kills at least a million people each year, primarily in sub-Saharan Africa. Another 300 million - 500 million people annually suffer the disease. Van Voorhis and colleagues have set out to limit the impact of the disease by developing new drugs, using knowledge and techniques provided by modern genomics. Van Voorhis, professor of infectious diseases has grants from the Medicines for Malaria Venture (MMV), the National Institutes of Health (NIH), and the World Health Organization/Tropical Diseases Research (WHO/TDR) to work on drug development, working with colleagues at UW and internationally.
For years, malaria responded to inexpensive drugs like quinine, chloroquine, and Fansidar, but since the 1970s, drug resistance has surfaced. Poor patients in hard-hit nations often can't afford a full course of medication, so they may purchase a few pills on the black market. The toughest parasites survive partial treatment and are transmitted to new victims. Says Van Voorhis, "The malaria parasite is able to mutate very, very quickly. Even as a new drug is developed, if it's not used properly, its potency is lost due to the emergence of resistance."
With drug resistance nullifying the effects of existing drugs, the time required for drug development—from beginning stages to actual use—is often impractically long. Van Voorhis and his colleagues, Michael Gelb, professor of chemistry and Frederick Buckner, associate professor of infectious diseases, set out to shorten the timeline by "piggybacking" onto drugs developed for other diseases that might also inhibit the malaria parasite.
The scientists searched extensively for new targets identifiable from the genome sequencing of the malaria parasite, always asking the question, "Are drug-like, patented inhibitors available for this target?" One enzyme, protein farnesyltransferase (PFT), had been studied as an anti-cancer target, and inhibitors of the enzyme were available from Bristol-Myers Squibb (BMS). The team began to focus on these inhibitors, concentrating on those that kill parasite cells but do not damage regular mammalian cells. Van Voorhis tested more than 300 compounds from BMS, synthesized a variety of related molecules, first for potency and then for potential use in mammals.
The researchers now have compounds that show great promise for drug therapy for malaria. They have moved on to testing efficacy, absorption, distribution, metabolism, and excretion, and performing early toxicology studies. The team hopes that compounds can enter pre-clinical development in the very near future.
The drug these scientists hope to develop will not be immune from the now-ubiquitous resistance factor. Says Van Voorhis, "It's clear that new drugs must be introduced through combination therapies—two or three at a time—to protect the new drug from the emergence of resistance."
To that end, Van Voorhis and his colleagues are testing drugs that might be combined with their future product. One class of drugs that shows promise is artemisinin, an effective but short-acting drug based on an ancient Chinese remedy extracted from sweet wormwood. Artermisinin combination therapy (ACT) has already been adopted as the therapy of choice in most African and Asian countries where malaria is endemic. New combinations, such as artemesinin-PFT inhibitor, will be valuable to these areas that bear the brunt of malaria's burden.
