December 22, 2003
Volume 81, Number 51
CENEAR 81 51 pp. 39-50

ISSN 0009-2347



Medicinal and combinatorial chemistry has increasingly become a mainstay of chemical research, accounting in part for the growing evolution of chemistry departments into departments of chemistry and biology.

One significant finding in 2002 was a report by Brian K. Shoichet of Northwestern University and coworkers that the potency of some inhibitory compounds depends on their tendency to form aggregates--and not simply on the affinity with which they bind to their targets, as had generally been believed [J. Med. Chem., 45, 1712 (2002)]. This year, Chun-wa Chung of GlaxoSmithKline, Stevenage, England, and coworkers showed that detergents, which break up aggregates, can reduce false positives when screening such compounds, and Shoichet's group determined a molecular mechanism for aggregation-induced inhibition [J. Med. Chem., 46, 3448 and 4265 (2003)]. Both findings could aid drug discovery.

In combinatorial chemistry, there's been an increasing focus on synthesis of natural-product-like compound collections (libraries) as potential founts of bioactive agents. Stuart L. Schreiber of Harvard University and coworkers devised a strategy for making natural-product-like libraries of unprecedented diversity [Science, 302, 613 (2003)]. They use core structures ("latent intermediates") that react with peripheral groups ("skeletal information elements") to generate compounds having all possible combinations of a set of both core skeletal frames and peripheral groups.

In pharmaceutical chemistry, Immucillin-H (BCX-1777) became "the first drug designed from an experimentally determined transition state to make it to the clinic," according to Vern L. Schramm of Albert Einstein College of Medicine, Bronx, N.Y., who led a group that created the leukemia agent.

Synthetic erythropoiesis protein (SEP, shown)--created by total synthesis (red and green) and modified with a polymer (blue)--could turn out to be the first completely synthetic protein-based compound to become a commercial pharmaceutical [Science, 299, 884 (2003)]. Designed and synthesized by Gerd G. Kochendoerfer of Gryphon Therapeutics, South San Francisco, and coworkers, SEP has longer lasting activity and is more potent in an animal model than is the anemia drug erythropoietin, which has a comparable backbone.

Among chemistry-related studies on infectious diseases this year, the mechanism of action of the antimalarial agent artemisinin was revised by Sanjeev Krishna of St. George's Hospital Medical School, London, and coworkers [Nature, 424, 957 (2003)]. They found that the drug targets a calcium-pumping enzyme, instead of attacking malarial parasites with nonspecific radical damage, as had been thought.

In a finding with possible implications for antibiotic resistance, Jon S. Thorson of the University of Wisconsin, Madison, and coworkers discovered that the bacterium that biosynthesizes the antibiotic calicheamicin has a bodyguard protein that sacrifices itself (via calicheamicin-induced cleavage) to disable free calicheamicin that might damage the bacterium [Science, 301, 1537 (2003)].

In research on protein-folding diseases, Surachai Supattapone and coworkers at Dartmouth Medical School, Hanover, N.H., found that RNA helps convert normal endogenous "cellular prion protein" to the infectious form that causes transmissible spongiform encephalopathies [Nature, 425, 717 (2003)]. The cellular factors involved were previously unknown.

Small-molecule compounds that inhibit protein misfolding related to neurodegenerative amyloidoses were identified by Jeffery W. Kelly and coworkers at Scripps Research Institute [Science, 299, 713 (2003)].

Carl T. Wild of Panacos Pharmaceuticals, Gaithersburg, Md., and coworkers discovered PA-457, the first clinical development candidate that targets HIV assembly and maturation [Proc. Natl. Acad. Sci. USA, 100, 13555 (2003)]. It could become the first in a new class of AIDS drugs: maturation inhibitors.

Richard A. Lerner and Paul Wentworth Jr. of Scripps and coworkers found that ozone is generated in arteriosclerotic plaques and may contribute to arterial disease via oxidation of cholesterol, low-density lipoproteins, and lipids found in such plaques [Science, 302, 1053 (2003)]. The findings add ozonation to several other proposed mechanisms for how plaque components become oxidized and cause disease.


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