Scientists seeking cures for parasitic diseases of the tropics describednew molecular targets for drugs, and new methods of developing drugsat last week's Third Annual Meeting of the National Institute ofAllergy and Infectious Diseases (NIAID) International Centers forTropical Disease Research in Washington.Although most of the millions of people in the tropics who couldbenefit from these medicines will not be able to afford them, somemedicines will find markets elsewhere, while the techniques used todevelop others may help bring more potentially lucrative medicines tomarket.For example, James McKerrow, of the University of California, SanFrancisco, is working on techniques to fight Chagas' disease, a chronictropical disease that debilitates and sometimes kills children. Thesetechniques will likely prove useful for treatment of heart attacks,cancer and arthritis.McKerrow's research focuses on cysteine protease enzymes. In arthritisand heart attacks, these enzymes are involved in the inflammationwhich damages joints and heart muscle, respectively. In parasites, theymediate transformation from one stage of the life cycle to the next.McKerrow has been developing compounds that inhibit the enzyme.One analog to the natural enzyme-inhibiting compound "dramaticallyreduced parasitemia in a mouse model of infection," said McKerrow."That confirms that cysteine protease inhibitors can be designed toselectively arrest parasite replication in vivo as well as in vitro." ButMcKerrow said he is several years away from starting clinical trials.Anti-malarial Drug May Replace ChloroquinTheresa Shapiro, professor of medicine at the Johns HopkinsUniversity School of Medicine, has enlisted a family of drugs calledthe topoisomerase II inhibitors to combat trypanosomes, leishmania,sleeping sickness and malaria. The major markets would includeroughly 7 million citizens who journey to malaria-infested countriesand the military. Troops returning from the Middle East and Somaliahave been infected with both malaria and leishmania, Shapiro said.Good antimalarial drugs, the chloroquins, already exist, but resistance,first noted in 1961, "has become a public health crisis," so thatreplacement drugs are badly needed, Shapiro told BioWorld.For treatment of leishmania, some analogs may have an advantage ofbeing able to penetrate the blood-brain barrier. This raises thepossibility of combating parasites that have invaded the central nervoussystem. Currently, the only anti-Tryposomal drugs that can cross theblood brain barrier are extremely toxic.The fluoroquinolones, a subset of topo II inhibitors, are widely used inthe U.S. against bacterial infections such as bacterial pneumonia andbacterial urinary tract infections.The topo II inhibitors act by inhibiting topoisomerases _ enzymes thattie and untie knots in DNA _ and otherwise manipulate strands ofgenetic material.Shapiro and research associate Annette Bodley, developed a new assayto screen topo II inhibitors, which she describes as non-radioactive,reproducible, quantitative and "the soul of simplicity." Themethodology has not yet been published.Host Cells Regain Control of CytokineOne interesting way that some parasites keep the host from killing themis by taking over the host cell's cytokine regulation system.Leishmania, and Trypanosoma cruzi, which cause frequently fatalinfections that are untreatable, are two examples. At the NIAIDmeeting, Steven G. Reed, of the Infectious Disease Research Institutein Seattle, described new studies in which host cells were helped toregain control of the cytokine systems, and subsequently eradicated theparasites. Immunex Corp., of Seattle, collaborated with Reed.The studies took place in mice and, most recently, in human peripheralblood monocytes. The technique may also be useful for combatingparasitic diseases in AIDS patients, such as Pneumocystis careeniipneumonia.Normally, the body's own supply of interferon gamma (IFN-g) wouldkill these parasites. But the parasites prevent this from happening byturning on production of three other cytokines that mitigate IFN-g'seffects. Researchers had demonstrated in animal studies that bothdiseases could be treated by neutralizing these cytokines individuallywith monoclonal antibodies. But the animals' immune systemsfrequently attacked the monoclonal antibodies.As an alternative, Reed used soluble Interleukin-4 (IL-4) receptor totreat mice that the researchers had infected with leishmania. IL-4 is oneof the cytokines that thwarts IFN-g. Control mice received monoclonalantibodies and saline, respectively. The rate of cure was 100 percent inthe IL-4 and monoclonal antibody arms of this study. IL-4 receptorsavoid the antigenicity problem since they are endogenous substances.Reed then tested this general method in peripheral blood monocytes(PBMC) obtained from five human patients who were infected withvisceral leishmaniasis, the most virulent form of the disease. Reedcultured the PBMCs from infected human patients, and added acompound which counteracted one of the cytokines that the parasiteshad turned on. The PBMCs responded by producing more INF-g,which killed the parasites.Leishmaniasis, sometimes fatal, infects about 12 million people in thetropics. Trypanosoma cruzi causes Chagas' disease, a chronic diseaseprimarily of children, characterized by skin lesions, headaches, apathy,convulsions and irregular fever. n
-- David Holzman Special to BioWorld Today
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