This was found in the Aug. 2, 1993 issue of Chemical and Engineering News.
Reprinted w/o permission.  (Page 3-4)

(C-60 is Carbon 60.  My computer can't make subscripts.)

_Fullerene Bioactivity C-60 derivative inhibits AIDS viruses_

A water-soluble derivative of buckminsterfullerene is active against HIV-1
and HIV-2, the human immunodeficiency viruses that cause AIDS, according
to work by two independant research groups.  The derivative is not a drug
candidate itself, but it offers a potentail lead for designing anti-HIV
agents, say scientists in the two teams.  This is the first example found
of biological activity by fullerenes.

The notion that a fullerene might be effective against the AIDS viruses
stems from two independent and entirely different lines of reasoning.
Researchers at the University of California, San Francisco, noted that
C-60 has dimensions and properties that suggest it might block the active
site of a key viral enzyme, HIV-1 protease.  Scientists at Emory
University in Atlanta recognized that a suitable derivatized C-60 would
share some properties with a class of large inorganic clusters that
inhibit another HIV enzyme, reverse transcriptase-and, as such, might also
inhibit the enzyme.

Both groups turned to chemistry professor Fred Wudl of the University of
California, Santa Barbara, to create the water-soluble derivative they
used.  Fullerenes are very hydrophobic and essentially insoluable in
aqueous media.  Wudl and coworkers developed a facile technique for
selectively functionalizing fullerenes.

Back-to-back papers in last week's _Journal of the American Chemical
Society_ [115, 6506 and 6510 (1993)] describe the model-building studies
at UCSF suggesting a C-60 derivative can inhibit protease, and the
synthesis at UCSB of a fullerene derivative to test this idea.  Research
at Emory on the derivative's biological activity is discussed in the
August issue of _Antimicrobial Agents and Chemotherapy_ [37, 1707 (1993)].

The UCSF discovery represents an unlikely intersection of three areas of
intense research activity:  fullerene chemistry, development of HIV-1
protease inhibitors, and rational drug design.

The idea of testing a fullerene for its ability to inhibit HIV-1 protease
originated with Simon H. Friedman, a graduate student in the laboratory of
George L. Kenyon, head of the UCSF pharmaceutical chemistry department.
Friedman was talking to a friend about the UCSF interdisiplinary effort to
find agents that block the protease.  "`We've looked at a lot of unusual
compounds," he noted, and the friend asked, "What are you going to try
next, a buckyball?'"  Her joke "prompted me to think about the
possibility," he says.

As Friedman thought about it, the idea grew less outlandish.  He points
out that HIV-1 protease can be roughly described as an open-ended cylinder
lined almost exclusively with hydrophobic amino acids.  Exceptions to this
hydrophobic trend are two aspartic acid residues that catalyze the attack
of water on the substrate's peptide bond.  A C-60 molecule has about the
same radius as the protease's active site and is, itself, hydrophobic.  So
C-60 should be good at slipping into the active site and blocking it.

Friedman created a computer model of C-60 and fitted the molecule into
the active site of HIV-1 protease.  The modeling process predicted
complexes "with C-60 squarely in the center" of the protease active site,
he says.  Working with Friedman and Kenyon at UCSF was Diane L. DeCamp, a
post-doctoral fellow in the laboratory of Charles S. Craik, a UCSF
pharmaceutical chemistry professor.  The work was supported by the
National Institutes of Health and the National Science Foundation.

The UCSF chemists then contacted Wudl.  Together with postdoctoral fellow
Rint P. Sijbesma and technician Gordana Srdanov, Wudl synthesized a
species he calls a "fulleroid" by adding a substituted diphenyldiazomethane
to C-60.  The resulting di (phenethylaminosuccinate) fulleroid is soluble
in water at pH 7 or above.  Structural characterization of this compound
by mass spectrometry, detailed in one of the _JACS_ papers, was done by
chemistry professor Charles L. WIlkins and graduate student J.A. Castoro
at the University of California, Riverside.

Further model building at UCSF indicated the substituted fulleroid would
bind to HIV-1 protease, with the fullerene ball lodged in the enzyme's
cylindrical active site and the changed succinate groups extending into
solution.  Experiments indicate the fulleroid inhibits the protease
competitively at 5.3 micromole per litre concentration, making it a good
lead compound for further drug design efforts.

Presumably, the principal force driving the association of the fulleroid
and HIV-1 protease is the hydrophobic interaction between the enzyme's
nonpolar active site surface and C-60.  Thus, the binding energy could be
increased by introducing specific electrostatic interactions between
fulleroid and enzyme-such as salt bridges between the catalytic aspartates
on the active site's floor and cationic sites on C-60 surface.

The UCSF chemists have modeled the interaction of a diamino C-60 with
HIV-1 protease, and found that electrostatic interactions between properly
orientated amino groups and the catalytic aspartates appear favorable for
binding.  Friedman is working on synthetic strategies for producing such a
fullerene derivative.

At Emory, chemistry professor Craig L. Hill and Raymond F. Schinazi, a
professor in the school of medicine's laboratory of biochemical
pharmacology, have been studying for a number of years the anti-HIV
properties of polyoxometalates, which are large, inorganic anionic
clusters.  Hill and Schinazi realized that fullerenes are similar in size
and shape to the polyoxometalates and, like them, hydrophobic.  A
fullerene that was suitably derivatized with anionic substituents might
also possess anti-HIV properties, the reasoned.

Hill contacted Wudl to produce such a derivative fullerene.  Its anti-HIV
activity was analyzed in Schinazi's laboratory, in research supported by
the Department of Veterans Affairs and the Public Health Service.

The Emory scientists discovered that Wudl's di(phenethylaminosuccinate)
fulleroid inhibits virus reproduction in acutely and chronically
HIV-infected immune system cells at about 7 micromole per liter and 11
micromole per liter concentrations, respectively.  By contrast,
zidovudine (AZT), a nucleoside analog inhibitor of reverse transcriptase,
is effective against acutely infected cells such as T lymphocytes but not
against chronically infected cells, Schinazi says.

Interestingly, the fullerene derivative was as effective against
AZT-resistant HIV as it was against AZT-sensitive virus.  This "lack of
cross-resistance with AZT suggests that combination studies of the
fullerenes with AZT could be considered in vitro," the researchers note.

The Emory studies suggest the fulleroid exerts a direct, virucidal effect
on HIV-1 and HIV-2, Hill says.  That is, while the fulleroid appears to
inhibit reverse transcriptase and HIV-1 protease, it also appears to kill
the viruses themselves.  The Emory research suggests this could be the
primary mode of action of the compound, Hill adds.

                                         --Rudy Baum