Bidding - the International Association of the Catalysis Societies

5) Highlights in Academic Output
C&EN Volume 82, Number 3, p. 62 (January 19, 2004)
Reagent cuts peptide bonds
Peptide amide bonds are notoriously unreactive under physiological conditions, but Nenad M. Kostic and
coworkers at Iowa State University, Ames, have now devised a reagent that cleaves peptides at pH 7 in a
sequence-specific manner [J. Am. Chem. Soc., published online Dec. 24, 2003]. The reagent (shown, red)
is a conjugate of a palladium(II) aqua complex, which cleaves amide bonds involving proline residues,
and -cyclodextrin, which binds aromatic side chains and positions the inorganic complex for specific
cleavage adjacent to a proline-phenylalanine sequence in a chosen peptide. The hydrolysis is fairly slow
but could be improved. "Our ultimate goal is to complement natural proteolytic enzymes with synthetic
inorganic-organic conjugates that have selectivities unachievable with natural enzymes," Kosti says. In
a related study, the site-selective hydrolysis of proteins with synthetic catalysts under physiological
conditions was also recently achieved by chemistry professor Junghun Suh and coworkers at Seoul
National University, Korea [J. Am. Chem. Soc., 125, 14580, 2003].
C&EN Volume 81, Number 36, p. 24 (September 8, 2003)
How Viagra works, structurally
Anti-impotence drugs like sildenafil (Viagra, shown) work by binding with an enzyme known as
PDE5, a member of the enzyme superfamily of phosphodiesterases. PDE5 thwarts erections by breaking
down cyclic guanosine monophosphate (cGMP) needed for smooth-muscle relaxation. Drug designers
have therefore looked for molecules like sildenafil that are structurally similar to cGMP. An even better
tool, however, would be a detailed picture of PDE5 itself bound with an inhibitor. Now, a team led by
Joong Myung Cho of CrystalGenomics, in Daejeon, South Korea, has determined crystal structures of
human PDE5 complexed with each of three different inhibitors: sildenafil, tadalafil, and vardenafil
[Nature, 425, 98 (2003)]. The topology of these structures is similar to that of an already-studied system
involving the related PDE4 and an inhibitor, but only 23% of the amino acid sequences in the enzymes'
catalytic regions are shared. This information should help researchers design better, more specific drugs
that inhibit PDE5, the authors say.
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