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HIV Inhibitors: Assembly Antiviral Inhibition of the HIV-1 Capsid Protein
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FOR IMMEDIATE RELEASE:
Monday, March 31, 2003
Abstract: During the assembly stage of the human immunodeficiency virus (HIV)
replication cycle, several thousand copies of the viral Gag polyprotein
associate at the cell membrane and bud to form an immature, non-infectious
virion. Gag is subsequently cleaved by the protease, which liberates the
capsid proteins for assembly into the polyprotein shell of the central core
particle (or capsid) of the mature virus. Viral infectivity is critically
dependent on capsid formation and stability, making the capsid protein a
potentially attractive antiviral target. We have identified compounds that
bind to an apical site on the N-terminal domain of the HIV-1 capsid protein
and inhibit capsid assembly in vitro. One compound,
N-(3-chloro-4-methylphenyl)-N'-{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methy
l)-sulfanyl]ethyl}urea) (CAP-1), is well tolerated in cell cultures,
enabling in vivo antiviral and mechanistic studies. CAP-1 inhibits HIV-1
infectivity in a dose-dependent manner, but does not interfere with viral ent
ry, reverse transcription, integration, proteolytic processing, or virus
production, indicating a novel antiviral mechanism. Significantly, virus
particles generated in the presence of CAP-1 exhibit heterogeneous sizes and
abnormal core morphologies, consistent with inhibited CA-CA interactions
during virus assembly and maturation. These findings lay the groundwork for
the development of assembly inhibitors as a new class of therapeutic agents
for the treatment of AIDS.
Journal of Molecular Biology
Volume 327, Issue 5 , 11 April 2003, Pages 1013-1020
Chun Tang1, Erin Loeliger1, Isaac Kinde1, Samson Kyere1, Keith Mayo2, Eric
Barklis2, Yongnian Sun3, Mingjun Huang3 and Michael F. Summers. 1 Howard
Hughes Medical Institute and Department of Chemistry and Biochemistry,
University of Maryland Baltimore County, 1000 Hilltop Circle, Baltimore,
Maryland 21250-5398, USA
2 Vollum Institute and Department of Microbiology, Oregon Health & Science
University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97201-3098, USA.
3 Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA
Offering the latest federally approved information on research,
clinical trials, and treatment.
Discovery Lays Groundwork for Potential New Class of Anti-HIV Drugs
Researchers supported in part by the National Institute of Allergy and
Infectious Diseases (NIAID) have identified compounds that in the laboratory
interfere with the assembly of HIV. This discovery lays the groundwork for
development of a potential new class of drugs-so-called assembly
inhibitors-to treat people with HIV/AIDS. Details of the work appear today in
the online version of the Journal of Molecular Biology
at:
http://www.sciencedirect.com/science/journal/00222836.
Michael F. Summers, Ph.D., a Howard Hughes Medical Institute investigator and
professor of biochemistry at the University of Maryland, Baltimore County,
led a team of undergraduate and graduate students in the effort. "This work
is yet another pivotal achievement on the part of Dr. Summers and his
students," says Anthony S. Fauci, M.D., NIAID director. "The fact that
undergraduate students played important roles in this research makes it even
more impressive." Dr. Summers and his student team have also successfully
solved the structures of three important HIV proteins and several other
components of HIV.
Although the current combination of reverse transcriptase inhibitors and
protease inhibitors used against HIV can effectively lower a patient's viral
load, lack of compliance and interactions with other drugs or diet can weaken the effect of these drug
"cocktails," allowing resistant strains of HIV to emerge, Dr. Summers
explains. Adding a new class of anti-HIV drugs such as assembly inhibitors
to the mix may help solve this problem.
The recently identified compounds bind to HIV-1 capsid proteins and prevent
these molecular building blocks from assembling into the HIV capsid, a
cone-shaped inner structure of the virusthat houses viral RNA, enzymes and other key viral components. Although the
compounds do not stop new viruses from assembling, they cause viruses to form
with defective capsids, and these abnormal viruses cannot infect new cells.
One compound in particular, CAP-1, is well tolerated by human cells.
Using powerful computers, Dr. Summers' team screened hundreds of thousands of
compounds, searching for those that might bind to the capsid protein. When
the computer search generated a short list of "hits," the researchers then
used a nuclear magnetic resonance machine to determine exactly where these
compounds attached to the capsid protein.
Although the compounds attached to a different area of the protein than
the one the team originally expected, experiments with the live virus and
human cells showed the compounds rendered HIV non-infectious.
Dr. Summers cautions that these compounds must be tested much more
extensively before an experimental assembly inhibitor could be developed for
clinical trials. "There is still a lot of chemistry to be done," Dr. Summers
says. "We still have to work to determine the best compounds and test their
toxicity in animals. But what is really exciting is that at least now there
is a clear path to follow for this new class of inhibitors."
Collaborators in this effort include the Oregon Health and Science University
in Portland and Achillion Pharmaceuticals of New Haven, CT, which conducted
the live HIV virus experiments. In addition to funding from NIAID, Dr.
Summers and his team received support from the National Institute of General
Medical Sciences.
NIAID is a component of the National Institutes of Health (NIH), an agency of
the Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose,
and treat infectious and immune-mediated illnesses, including HIV/AIDS and
other sexually transmitted diseases, illness from potential agents of
bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.
Reference: C Tang et al. Antiviral inhibition of the HIV-1 capsid protein.
Journal of Molecular Biology 327(5):1013-20 (2003).
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