September 28, 1999 -- Using three-dimensional images of a key AIDS virus protein as their guide, a team of Howard Hughes Medical Institute (HHMI) investigators has found several chemical compounds capable of preventing the human immunodeficiency virus (HIV) from fusing with human cells. Without the ability to fuse to human cells, HIV cannot cause infection.
"Seeing the structure of this protein, gp41, suggested the whole experimental design," said Stephen Harrison, an HHMI investigator at Children's Hospital in Boston and Harvard University. In 1997, independent research teams led by HHMI investigators Don Wiley, also of Children's Hospital and Harvard University, and Peter Kim at the Whitehead Institute for Biomedical Research determined the three-dimensional structure of gp41 using x-ray crystallography.
HIV infects immune system cells that bear the CD4 molecule on their surface. A viral glycoprotein - a complex of protein and carbohydrate - called gp120 recognizes and binds to CD4, which triggers a change in the shape of the associated viral glycoprotein, gp41. These subsequent structural changes in gp41 must occur in order for HIV to enter a human cell.
In the October 1999 issue of Nature Structural Biology, Harrison, Wiley, fellow HHMI investigator Stuart Schreiber, and members of their laboratories at Harvard University, describe the creation of a library of more than 61,000 chemical compounds that could potentially fit into a deep pocket within the gp41 structure. Harrison and his colleagues screened each of the compounds and identified several that could prevent HIV infection by interfering with gp41.