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Scientists Target Microbe With Sleeker Antisense Agent

Date:
June 29, 1999
Source:
University Of Rochester
Summary:
Scientists at the University of Rochester have created a remarkably short "antisense" compound, just a few nucleotides long, that targets the strain of pneumonia which kills many AIDS patients and others with weakened immune systems. While the compound is in its earliest stages of development, scientists believe the work marks one step toward an era when tiny artificial RNA molecules act as selective medications that knock out vital sections of molecules which organisms rely on to invade their human hosts.

Scientists at the University of Rochester have created a remarkably short "antisense" compound, just a few nucleotides long, that targets the strain of pneumonia which kills many AIDS patients and others with weakened immune systems. While the compound is in its earliest stages of development, scientists believe the work marks one step toward an era when tiny artificial RNA molecules act as selective medications that knock out vital sections of molecules which organisms rely on to invade their human hosts.

Led by Douglas H. Turner, a team of researchers at the University tested its technology, where scientists create a complementary copy of a strand of RNA in an attempt to knock out a specific RNA molecule from the organism Pneumocystis carinii. This fungus is an opportunistic pathogen that lives dormant in the lungs of healthy individuals, but flourishes in people with impaired immune systems, causing pneumonia and leaving its victims gasping for breath. More than half of AIDS patients are infected by the microbe at some point in their lives, and more than 20 percent ultimately die from an infection; cancer patients and people who have received organ transplants are also susceptible.

The Rochester team blocked the formation of a strand of RNA that the organism needs to survive. While the work was done in a test tube, it's a first step toward designing drugs to treat this class of infections. The need for new anti-fungal medications is clear, says Turner: "The problem is that the bugs evolve. They're getting resistant to the standard treatments."

The National Institutes of Health (NIH) funded the study conducted by Turner, a professor of chemistry; Stephen M. Testa, formerly a post doctoral research associate now at the University of Kentucky; and Sergei M. Gryaznov, a chemist from Geron Corp., a California bio-tech company that supplied molecules for the project. The results were published recently in the Proceedings of the National Academy of Sciences.

The team designed a molecule that targets an RNA strand responsible for making ribosomes, the cellular structures that manufacture proteins. Without its protein-making machinery, the organism would die. The synthesized molecule, a phosphoramidate, resembles and impersonates the organism's RNA, interlocking with P. carinii's RNA like the teeth of a zipper. In the chemical reaction that follows, the molecule essentially harpoons the target, splitting it into pieces that cannot function, going a step further than most antisense agents, which simply interweave with the target molecule.

"It's fascinating that you could use something that is very similar to what is already in our bodies --RNA and DNA -- as a potential drug. It's pretty amazing," Testa says.

Typically, scientists have made antisense agents that are 15 to 20 nucleotides long to bind to large molecules such as RNA. Scientists have believed that the longer the molecule, the lesser the likelihood of unwanted side effects from targeting the wrong RNA strand. Such side effects include rashes, fever and fatigue in AIDS patients, and bone marrow suppression in cancer patients. Turner's team discovered that the molecule could be kept remarkably short and still bind to a targeted section of RNA more strongly and with greater selectivity than a larger molecular strand. In their experiments, an unusually small chain of only six nucleotides does the work that traditionally requires much larger molecules.

"This is exciting because if you figure out a general way to target RNA, then, in theory, you can target almost any disease," says Turner. "Our approach is a new way of designing drugs, built on 15 years of basic research. Even as drugs that use an antisense scheme begin to go on the market, we're trying to create newer, more sophisticated compounds."

They created the more efficient molecule by designing it to form an RNA complex that the P. carinii target regularly ensnares, similar to the way a Venus fly trap captures its prey. The molecule is able to tap interactions usually unavailable as RNA and other molecules bind to each other, allowing scientists to use a shorter, sleeker, and less expensive agent.

In this study, the snippet of P. carinii's RNA that the team targets is not found in humans or other mammals, making it an attractive avenue for treating the infection. Turner and his co- authors have filed a patent application for their new type of antisense agent and are continuing their studies. Their next goal is to reproduce the reaction in the cells of the organism, taking advantage of recent work by scientists at New York University who have learned how to grow the organism in the laboratory. Turner is hopeful that more research will make the technology a viable treatment for people infected with P. carinii.

The team launched its work on P. carinii with physician Frank Gigliotti and researcher Constantine Haidaris in the University of Rochester School of Medicine and Dentistry. Gigliotti's group is known internationally for its understanding of the basic biology of the organism, and the team is developing a vaccine against the microbe. In an additional effort to protect patients from infection, Gigliotti's group together with colleagues from the Trudeau Institute in Saranac Lake, N.Y., has shown how to use the organism to prevent infection in mice. Gigliotti's team currently has about $3 million in funding from the NIH to understand precisely how the organism causes pneumonia and to continue its research toward a vaccine for humans.


Story Source:

The above story is based on materials provided by University Of Rochester. Note: Materials may be edited for content and length.


Cite This Page:

University Of Rochester. "Scientists Target Microbe With Sleeker Antisense Agent." ScienceDaily. ScienceDaily, 29 June 1999. <www.sciencedaily.com/releases/1999/06/990629085434.htm>.
University Of Rochester. (1999, June 29). Scientists Target Microbe With Sleeker Antisense Agent. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/1999/06/990629085434.htm
University Of Rochester. "Scientists Target Microbe With Sleeker Antisense Agent." ScienceDaily. www.sciencedaily.com/releases/1999/06/990629085434.htm (accessed July 31, 2014).

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