January 16, 1998
New Drug Target May Cause HIV to Knuckle Under
The researchers, led by Hughes investigator Michael
F. Summers at UMBC, used nuclear magnetic resonance (NMR)
spectroscopy to determine the three-dimensional structure of the HIV
nucleocapsid binding to the virus' genetic material, RNA. NMR helps
scientists construct a picture of a protein by supplying information
about the relative distance between individual atoms in the
protein.
"This is the first structural information that shows how HIV viral
proteins recognize the viral genome," said Summers. He and colleagues
from Syracuse University published their work in the January 16 issue
of the journal Science.
After HIV infects a cell, the HIV nucleocapsid, which is located
inside the virus, packages RNA into the core of newly formed infectious
viral particles, which then move on to infect other cells. Scientists
may be able to design drugs that keep RNA out of the nucleocapsid's
grasp, offering a real chance of preventing the virus from spreading,
said Summers.
In 1992, Summers' team determined the structure of the HIV
nucleocapsid. Other labs showed that the nucleocapsid recognizes and
binds to the viral RNA genome. Further research showed that the
nucleocapsid recognizes viral RNA by homing in on the packaging
domain—a small nucleotide sequence in the viral RNA.
In order to learn more about this critical protein-RNA interaction,
Summers' team decided to take a closer look. Working with Philip N.
Borer and Lucia Pappalardo at Syracuse, Summers and UMBC colleagues,
Roberto N. De Guzman, Zheng Rong Wu and Chelsea C. Stalling, showed
that the nucleocapsid grasps the packaging domain on RNA using two
"zinc knuckles." The term zinc knuckle was coined by Summers to
describe that portion of the nucleocapsid that requires zinc to
function.
The zinc knuckles are an attractive drug target, Summers says,
because the nucleocapsid needs zinc atoms in order for it to fold and
function properly. "The zinc knuckle domains are intolerant of
mutations," Summers said. "They are a good target because it is
unlikely that the virus would be able to mutate the zinc knuckle
domains to evade an ativiral drug."
Several pharmaceutical companies have already asked Summers to test
chemical compounds in their inventory to see if any can pry zinc out of
the nucleocapsid. "We have tried a number of different compounds, but
none of them has been satisfactory because they remove zinc from a
number of different proteins found in cells."
A more specific class of antiviral drugs that aims to knock zinc out
of the nucleocapsid protein is now undergoing clinical trials in the
United States and the United Kingdom.
Summers believes that the structural data that he and Borer have
published in Science may offer a blueprint for a new generation
of antiviral drugs that compete with RNA for the nucleocapsid binding
site. The work may also provide a helping hand for those working to
develop new drugs to treat other retroviruses or leukemia viruses. "The
more targets that drug developers have to shoot at, the better the
chance that more effective drugs will be developed," Summers said.
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