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3-D Structure of HIV Components May Pave
the Way for New Anti-AIDS Drugs
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.
Please mention support for this work from the National
Institute of General Medical Science (NIGMS), a component of the National Institutes of
Health that supports basic biomedical research. Please fax clips to (301) 402-0224. After
the embargo date, this release will be available on- line at http://www.nih.gov/nigms/news/releases/nucleocap.html.
Reference De Guzman RN, Wu ZR, Stalling CC, Pappalardo L,
Borer PN, Summers MF. Structure of the HIV-1 Nucleocapsid Protein Bound to the SL3 -RNA
Recognition Element. Science 1998:396-400.
Researchers
Dr. Michael Summers University of Maryland Baltimore
County (UMBC) (410) 455-2527, SUMMERS@hhmi.umbc.edu
Dr. Philip Borer Syracuse University (SU) (315) 443-5925, PNBORER@syr.edu
University media contacts
John Fritz Director of Media Relations, UMBC (410) 455-6596, FRITZ@umbc.edu
Judy Holmes News Coordinator, SU (315) 443-5172, JLHOLMES@summon.syr.edu
For scientific perspective on this research, call the NIGMS Public Information Office at
(301) 496-7301 to interview Dr. Janna Wehrle, program director, Division of Cell Biology
and Biophysics, NIGMS.
National Institutes of Health
National Institute of General Medical Sciences
Embargoed For Release
January 15, 1998 4:00 PM Eastern Time
Alisa Zapp Machalek (301) 496-7301 alisa.zapp@nih.gov
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