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 virus that 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 can not 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.
Reference: C Tang et al. Antiviral inhibition of the HIV-1 capsid protein. Journal of Molecular Biology 327(5):1013-20 (2003). Published online at http://www.sciencedirect.com/science/journal/00222836.
NIAID is a component of the National Institutes of Health (NIH). 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.