In 1997, NIGMS-supported scientists determined the detailed, three-dimensional structure of gp41, a protein responsible for the infectivity of HIV. The structure revealed an attractive drug target--a deep pocket, that, if blocked, would likely shut down gp41 and thwart HIV infection. This year, two groups used this structure to rationally design molecules that block the action of gp41. These molecules may serve as precursors for entirely new anti-AIDS drugs.
One of the groups, lead by Dr. Peter Kim at MIT's Whitehead Institute (who also lead one of the teams that determined the structure of gp41), took advantage of the fact that normal proteins exist in only one conformation, as if they were all "right handed." Dr. Kim's group designed small protein mimics that are "left-handed." Several of these molecules bind to gp41 and, in test-tube experiments, block HIV infectivity.
Because the molecules are unnatural, left-handed compounds, they do not trigger an immune response and are less susceptible to attack by the body's natural degradative enzymes. They are also small enough to be delivered orally, in contrast to T-20, a peptide that targets gp41 and is in Phase II clinical trials, but must be injected into patients.
Using an entirely different approach, Dr. Stephen Harrison of Harvard University, generated a combinatorial chemical library with tens of thousands of small (non-protein), organic molecules. Some of these compounds, when fused to a fragment of gp41 known to bind to the entire gp41 protein, attached to the complete gp41 and prevented infection.
Both reports provide hope that one day we may have yet another class of drugs in the anti-HIV arsenal.
Eckert DM, Malashkevich VN, Hong LH, Carr PA, Kim PS. Inhibiting HIV-1 Entry: Discovery of D-Peptide Inhibitors that Target the gp41 Coiled-Coil Pocket.
Ferrer M, Kapoor TM, Strassmaier T, Weissenhorn W, Skehel JJ, Oprian D, Schreiber SL, Wiley DC, Harrison SC. Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements.
Nature Structural Biology 1999;6(10):953-9.
Buzko OV, Shokat KM: Blocking HIV entry.
Nature Structural Biology 1999;6(10):906-8. (News & Views section)
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This page last reviewed on
12/4/2018 4:29 PM
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