THE next generation of AIDS drugs may be free of two dreaded side effects.
Today鈥檚 drugs can cause disfiguring fat redistribution in the body and diabetes.
But researchers in Missouri have pinned down the reason for these problems, and
say that tinkering with the chemical make-up of the drugs could banish the side
effects for good.
People with HIV are given drugs called protease inhibitors which are designed
to gum up HIV protease, an enzyme that the virus needs to replicate. But they
can also cause metabolic disorders, including a redistribution of fat from the
face and limbs to the torso. Some patients grow a 鈥渂uffalo hump鈥� of fat on their
upper back. Most also become insulin resistant鈥攕o their cells do not
absorb sugar properly鈥攁nd many become fully diabetic.
Now Mike Mueckler and his colleagues at Washington University in St Louis
have shown that protease inhibitors cause the problems by sabotaging a protein
that shuttles sugar into cells. They had noticed that patients鈥� symptoms
resemble those of a strain of mice lacking a protein called glucose transporter
4 (Glut4), which carries glucose across the membranes of muscle and fat cells.
These mice do not have any fat and are insulin resistant. 鈥淪o we thought it鈥檚
possible the protease inhibitors were causing the syndrome by blocking Glut4 in
people,鈥� Mueckler says.
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The Glut4 protein is normally stored inside the cell until it gets a signal
from insulin to start transporting sugar. The researchers suspected that by
binding to Glut4, protease inhibitors interrupt this process. Sure enough, when
they applied a widely prescribed protease inhibitor to cultured mouse fat cells,
the drug slashed the rate at which the cells absorbed glucose from their growing
medium when prompted by insulin.
To make sure Glut4 was the drug鈥檚 target, they added the gene for this
protein to frog eggs, which have no Glut4 of their own and do not respond to
insulin. The eggs inserted the protein in their cell membranes and were able to
take up glucose well even without insulin. But adding the protease inhibitor cut
the rate of absorption by 45 per cent. The results will appear in a future issue
of The Journal of Biological Chemistry.
鈥淚t鈥檚 a very interesting finding,鈥� comments Jonathan Purnell, who directs the
weight disorders clinic at the University of Washington in Seattle. 鈥淚t could
explain some of the insulin resistance we see.鈥� However, he points out that it鈥檚
not clear how binding to Glut4 could alter fat distribution.
The only way to be sure how many of the drugs鈥� side effects are caused by the
blocking of Glut4 would be to design a protease inhibitor that doesn鈥檛 bind to
it. Mueckler hopes to collaborate with a pharmaceuticals company to do this. 鈥淲e
can鈥檛 really predict what modifications will be necessary, but by trial and
error, it should be possible.鈥�