COLLEGE STATION, Texas, Nov. 21, 2011 – A powerful topical
preventative for HIV, the virus that causes AIDS, could be a step
closer to clinical trials thanks to a newly discovered molecular
compound that research at Texas A&M University and the Scripps
Research Institute shows dissolves the virus on contact.
The ability of the synthetic compound known as “PD 404,182” to
break apart the AIDS-causing virus before it can infect cells was
discovered by Zhilei Chen, assistant professor in the university’s
Artie McFerrin Department of Chemical Engineering, and her team of
researchers. Their findings appear in the November online edition
of “Antimicrobial Agents and Chemotherapy,” a journal of the
American Society for Microbiology.
“This is a virucidal small-molecule compound, meaning that it
has the ability to kill a virus; in this case that virus is HIV,”
Chen says. “Basically, it acts by breaking the virus open. We found
that when HIV comes in contact with this compound, it breaks open
and loses its genetic material. In a sense, the virus ‘dissolves,’
and its RNA becomes exposed. Since RNA is pretty unstable, once it
is exposed it’s gone very quickly and the virus is rendered
non-infectious.”
In other words, the compound works by quickly ripping open the
virus before it can inject its genetic material into a human cell.
What’s more – and perhaps even more important – the compound, Chen
explains, achieves this by acting on something within the virus
other than its viral envelope protein, meaning that the virus can’t
alter its proteins to bolster its resistance – something that’s
made HIV notoriously difficult to treat.
“We believe this compound is not working on the viral protein of
the viruses but on something else common in all the viruses on
which we tested it – some cellular material common in these
viruses,” Chen notes. “Because this compound is acting on a
component that is not encoded by the virus, it will be difficult
for the virus to evolve resistance against this compound.”
While not a cure for HIV, the compound demonstrates significant
potential for use as a preventative, specifically in the form of a
topical gel that could be applied in the vaginal canal, Chen
explains.
“We conducted a number of tests to demonstrate that this
compound remains active in vaginal fluid and is not rendered
ineffective,” Chen says. “In the form of a vaginal gel, the
compound would serve as a barrier, acting almost instantaneously to
destroy the virus before it could infect a cell, thereby preventing
HIV transmission from one person to another.”
Surprisingly, Chen and her team did not set out to discover an
HIV preventative. Instead, they were conducting screenings of
molecules for use in potential drug therapies targeting hepatitis C
virus, which causes the dangerous and often fatal disease of the
liver. Employing a screening system developed by Chen, the team
screened thousands of molecular compounds, in search of those that
could block aspects of the HCV life cycle.
During the course of the screenings, the team made an
interesting discovery – not only was PD 404,182 an HCV inhibitor,
it also worked on lentiviruses (the group’s negative control in its
experimental procedures). Intrigued by that finding, Chen then
tested PD 404,182 on HIV, which itself is a lentivirus and found
the compound to be even more effective on HIV than on HCV.
“We believe PD 404,182 acts through a unique and important
mechanism,” Chen notes. “Most of the known virucidal compounds
interact with the virus membrane, but our compound does not appear
to interact with the virus membrane. Instead, it bypasses
interaction with the membrane and still compromises the structural
integrity of the virus.”
The ability of the compound to avoid interaction with the virus
membrane is important because human cells have similar membranes,
Chen notes. If the compound were to disrupt the structure of the
virus membrane, it could also disrupt and ultimately kill human
cells. PD 404,182 doesn’t interact with these membranes and is
therefore a more attractive option for clinical treatment, Chen
says.
As is the case with any potential pharmaceutical, several key
steps are still needed before it winds up on drug store shelves. In
addition to several rounds of animal studies to ensure the compound
is safe for humans, further collaborations with chemists are needed
to continue to improve the efficiency of the compound. Chen says.
What’s more, Chen also plans to further explore the mechanism by
which PD 404,182 breaks apart HIV.
This work is collaboration between Chen’s team, consisting of
graduate students Ana Maria Chamoun and Rudo Simeon, postdoctoral
associate Karuppiah Chockalingam, and Professor Philippe Gallay’s
team at the Scripps Research Institute.
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Contact: Zhilei Chen at (979) 862-1610 or via email: zchen4@tamu.edu or
Ryan A. Garcia at (979) 845-9237 or via email: ryan.garcia99@tamu.edu.