BioChemist Searches For Clues to HIV Binding:
Date: Jan. 16, 2001
Finds Protein Structural Flexibility May Be Key
By: Chris Curran
Phone: (513) 556-1806
Archive: Research News
The search for an effective way to prevent or treat infections with the AIDS virus has been a frustrating one for many scientists, but the search is now focused right down to the molecular level. And a University of Cincinnati biochemist is helping to unlock the secrets of a key protein in the infection process.
The protein is known as gp-120. That means it's a sugar-coated protein with a mass of 120 kilodaltons. Pearl Tsang, associate professor of chemistry, and her colleagues focused in one portion of that protein, just 15 amino acids in length along a section known as the "V3 loop."
"That specific region [the V3 loop] is critical to infection, because that's the part of the virus that binds to receptor proteins involved in infection of the host immune cells," said Tsang. "If we can understand how it interacts with the receptor on these immune cells, that would allow drug companies to design drugs to block that interaction."
The basic idea is simple. Prevent the AIDS virus HIV from getting inside the immune cells. Block the virus, and you prevent infection. A simple idea, but it's a very tough task for researchers like Tsang. "It's slow-going," said Tsang. "It's never been easy, because this is a difficult system to study. But it's important in finding out what kinds of therapy might work."
Tsang uses nuclear magnetic resonance (NMR) and other spectroscopic techniques to study the structure and binding characteristics of the V3 loop peptide. What she and her collaborators discovered was that no particular structure is adopted by this peptide.
"The V3 loop region of this protein appears to be structurally flexible. That's astounded a lot of people," said Tsang. "There's no single predominant structure."
That means that this region of the HIV gp120 protein can change its shape as needed to bind to its target receptor on the host cell. "It appears that it's important that this region be flexible."
In fact, when the researchers tried to lock the protein into a particular structure, that inhibited binding. "It's a surprising result," admitted Tsang. "But other groups using different methods are now beginning to see this as well."
The findings are significant in terms of drug design, because they rule out using the structure of the 15-peptide sequence as a logical target for anti-HIV drugs. "We have to look elsewhere," concluded Tsang. "You can't design something to attack this. Or, you need to look at post-binding stages binding after it (the V3 loop) reaches its final conformation."
Her findings were published recently in the Journal of Biological Chemistry (11/24/00). The co-authors were Gang Wu, a graduate student at UC; Roger MacKenzie at the Institute for Biological Sciences in Ottawa, Canada; and Paul Durda at Massachusetts General Hospital. The research was funded by the National Institutes of Health.
Program for Women Undergraduates Helps Research Effort
Tsang received some important help in her research from biochemistry undergraduate Fannie Papatoli last summer.
Papatoli was one of several UC undergraduates chosen for Research Experience for Women Undergraduates program sponsored by UC's Women in Science and Engineering (WISE) group. "It's an excellent program," said Tsang. "We get them to think about what they can do with a science degree. Mentoring women in science is an important issue, and I'm glad to take part."
Papatoli's project focused on optimizing the conditions for collecting the specific peptide that Tsang studies. That involves some very specialized procedures for protein synthesis, purification and analysis. "This program gave me the opportunity to see what being a scientist means," said Papatoli. "I had the chance to learn how to use the various equipment in the lab - chromatography and peptide synthesis equipment and get familiar with the lab work and techniques used. I was impressed with the organization of the research program, and I think that its continuation is of utmost importance for the benefit of forthcoming scientists."