As HIV appears to outmaneuver even the latest drug combinations, researchers are scrambling for new attack strategies. New molecular details about one HIV protein may provide just that--the basis for an entirely new class of highly specific anti-AIDS drugs.
Scientists working with support from NIH's National Institute of General Medical Sciences have determined the three-dimensional molecular structure of the HIV nucleocapsid protein bound to the virus' genetic material (RNA, or ribonucleic acid). The nucleocapsid protein is responsible for stuffing viral genes into new viral particles. The protein is a prime target for anti-AIDS drugs, because previous studies have shown that when it is crippled, HIV cannot spread to other cells. New drugs that block the action of the RNA component could be equally important.
The detailed structure of the protein-RNA complex, determined using a technique called nuclear magnetic resonance (NMR) spectroscopy, is published in the January 16 issue of Science.
"The structure is significant for two main reasons. First, it provides molecular insights into how the protein recognizes and binds to [a specific site on viral] RNA. Second, it provides a structural basis for the development of drugs that are designed to disrupt this recognition and binding, and thus prevent the spread of the virus," said Dr. Michael F. Summers, lead author of the study and a professor of biophysical and bioinorganic chemistry at the University of Maryland Baltimore County (UMBC). Dr. Summers is also an associate investigator of the Howard Hughes Medical Institute.
Like a father recognizing his child in a crowded classroom, nucleocapsid plucks from the infected cellular melange only the specific viral RNA needed to form new viral particles. Nucleocapsid recognizes and binds to only the few RNA strands that contain a site called the packaging domain, said coauthor Dr. Philip N. Borer, professor of chemistry and biophysics at Syracuse University.
Nucleocapsid uses two "zinc knuckles"--special structures that each require a zinc atom to function--to grip the packaging domain on viral RNA. The protein winds the RNA to form the core of new virus particles, which eventually burst forth from an infected cell.
"Dr. Summers had already shown [in a 1993 Nature article and in later publications] that removing the zinc, so that the knuckles fall apart, results in uninfectious viral particles. The particles form, but their genetic material is missing, so they can't spread to other cells," said Dr. Janna Wehrle of the NIGMS Division of Cell Biology and Biophysics.
Pharmaceutical companies took an immediate interest in these previous results, said Dr. Summers. "Nucleocapsid has already been targeted by antiviral agents that eject zinc from the protein, some of which are undergoing clinical tests in the U.S. and U.K.," he said.
Even more effective drugs may be designed specifically to block the molecular embrace between nucleocapsid and RNA. Molecular details of this interaction reveal that the goal is more than theoretical--the viral interaction is completely different from normal interactions in human cells. This indicates that such custom-designed drugs may not only stop viral spread, but also could be safe for patients.
The Summers and Borer groups also have determined the structures of the isolated protein and RNA components. Because HIV and other retroviruses require a nucleocapsid protein to package viral RNA, these structures may not only underlie a new generation of anti-AIDS drugs, but also may accelerate drug development for some types of leukemia and other retroviral diseases.
Other contributors to the work are Roberto N. DeGuzman, Zeng Rong Wu, and Chelsea C. Stalling of UMBC and Lucia Pappalardo of Syracuse University.
Journal
Science