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Study finds HIV protease inhibitor drugs may adversely affect the scaffolding of the cell nucleus

UCLA scientists, along with collaborators from Purdue University, have demonstrated that HIV protease inhibitors crucial drugs for HIV treatment block a cellular enzyme important for generating the structural scaffolding for the cell nucleus.

Published in the July 16 early edition of Proceedings of the National Academy of Sciences, these biochemical findings may offer insights into the side effects of HIV protease inhibitors, including metabolic syndrome and regional losses of some of the bodys fat tissue. These side effects occur in up to one-third of patients taking anti-HIV drug regimens.

We show, for the first time, that certain HIV protease inhibitor drugs directly inhibit an enzyme called ZMPSTE24, which is important for generating the structural scaffolding supporting the cell nucleus, said Catherine Coffinier, Ph.D., study author and an assistant researcher at the David Geffen School of Medicine at UCLA.

UCLA researchers added HIV protease inhibitors to cultures of mouse and human fibroblast cells. They found that the inhibition of ZMPSTE24 by the HIV protease inhibitor drugs led to an accumulation of prelamin A, which is a precursor to mature lamin A a key molecule in the structural scaffolding for the cell nucleus. ZMPSTE24 is a membrane-bound intracellular zinc metalloproteinase that is required for the conversion of prelamin A to mature lamin A.

Interestingly, researchers found that the accumulation of prelamin A was exaggerated in cells that contained half the normal amount of ZMPSTE24.

Genetic defects in ZMPSTE24 in humans lead to an accumulation of prelamin A and cause a host of disease phenotypes, including partial loss of body fat depots and metabolic syndrome.

The fact that HIV protease inhibitors block ZMPSTE24 and have been associated with side effects similar to those observed with a genetic deficiency in ZMPSTE24 is intriguing, said Loren Fong, Ph.D., study author and an associa
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Contact: Rachel Champeau
rchampeau@mednet.ucla.edu
310-794-0777
University of California - Los Angeles
16-Jul-2007


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