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 domaina 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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