NEWS OF THE WEEK to synthesize peptides of more than about 100 residues with this method. Proteolytic enzymes, which catalyze hydrolysis of peptide bonds, can be used in "reverse mode" to catalyze peptide-bond formation, eliminating the need to use multiple protecting groups in fragment condensation. However, proteolytic enzymes often exhibit residual hydrolytic activity, causing troubling side reactions. Hirschmann, Smith, Benkovic, and coworkers have now developed an antibody that catalyzes formation of peptide bonds but doesn't cause residual hydrolytic side reactions. The antibodies catalyze the ligation of L- or D-tryptophan amide with p-nitrophenyl esters of Nacetylated L- or D-valine, -leucine, or -phenylalanine in aqueous solution. The ability to catalyze reactions of D amino acids—and potentially other nonnatural amino acids—is an advantage of catalytic antibodies over proteolytic enzymes, including recently developed genetically engineered proteases. Peptide yields range from 44 to 94%— high enough to permit isolation and Michael Freemantle characterization. Only dipeptides are produced, but the researchers believe catalytic antibodies could potentially be developed to make larger peptides as well. Commenting on the work, James P. Tarn of the department of microbiology Two independent research teams have and immunology at Vanderbilt Univerdevised new catalytic antibodies as sity, Nashville, who specializes in pepaids to organic synthesis. One team has tide synthesis, says further developdeveloped antibodies that catalyze ment is needed if antibodies are to find peptide bond formation, and the other practical use in fragment condensation. has developed catalytic antibodies for a He says it is not yet clear if the techthermodynamically disfavored elimi- nique will be applicable to larger peptides and that nitrophenyl ester reacnation reaction. The antibody-catalyzed peptide syn- tants could be problematical because of thesis, having yields as high as 94%, their tendency to cause side reactions. was achieved by chemistry professors However, the work, says Tarn, repreRalph F. Hirschmann and Amos B. sents "a wonderful beginning" and "a Smith III of the University of Pennsyl- very elegant and useful approach." vania, Philadelphia, and Stephen J. In a separate study, a catalytic antiBenkovic of Pennsylvania State Univer- body for disfavored elimination reacsity, University Park [Science, 265, 234 tions was developed by Benjamin F. (1994)]. Cravatt, Dale L. Boger, Richard A. LerThe peptide-forming catalytic anti- ner, and coworkers of the departments body represents a potentially new ap- of molecular biology and chemistry at proach to fragment condensation, a Scripps Research Institute, La Jolla, Calif. technique in which peptide fragments [/. Am. Chem. Soc., 116, 6013 (1994)]. The are linked to form larger peptides. antibody catalyzes syn elimination of an Rates of fragment condensation reac- acyclic compound to a cis olefin. In a syn tions are often slow, and the need to elimination, the two "leaving groups" use multiple hydrophobic protecting on adjacent carbon atoms are on the groups tends to make large peptides same side of the plane defined by the insoluble in water. Thus, it is difficult carbon skeleton. the toxicity and analysis of inorganic lead in wine. Until now, instrumental techniques have not been sufficiently sensitive to measure organolead." Lobinski and his colleagues used capillary gas chromatographic equipment with an on-line microwaveinduced plasma atomic emission detector coupled with a custom-designed wet chemical procedure to discriminate between Pb2+ picked up by the grapes from soil minerals and different species of organolead originating from automobile exhausts. The toxicity of inorganic lead in wine is well established. Organolead compounds are more toxic, however, because they are soluble in lipids. They therefore readily accumulate in fatty tissue, especially in the brain. The Nature paper suggests that the 1970s vintages might pose a health hazard if consumed in large quantities. But the most ardent wine lovers probably need not worry, Lobinski points out, since such vintages are now rare, expensive, and only available, if at all, at wine auctions.
Two new uses found for catalytic antibodies
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JULY 11,1994 C&EN
Syn elimination is rare in acyclic systems, and when it does occur it generates predominantly trans, not cis, olefins. Syn elimination to a cis olefin is thermodynamically disfavored by up to 5 kcal per mole (compared with the more common anti elimination to a trans olefin)—making it likely the most energetically demanding reaction yet catalyzed by an antibody. Chemistry professor William H. Saunders Jr. of the University of Rochester, N.Y., whose research interests include mechanisms of elimination reactions, says the Scripps researchers "make a convincing case that they have obtained a syn-to-cis elimination under circumstances where one would expect little or none." From a synthetic standpoint, he says, "the usefulness of the antibodycatalyzed reaction depends on its generality. Are strong activating groups . . . required? How much substrate variation will a given antibody tolerate before losing its catalytic ability? If the substrate specificity is stringent, how easy will it be to generate a new antibody for each synthetic application?" Nevertheless, says Saunders, "This result is fascinating, and . . . its mechanism and potential applications should certainly be further explored." Stu Borman
Fiberglass listed as a possible carcinogen The National Toxicology Program (NTP), in its annual report to Congress on carcinogens, has listed fiberglass— used in the vast majority of U.S. homes as insulation—as a material "reasonably anticipated to be a carcinogen." Manufacturers of fiberglass charge the government is using outmoded criteria for determining which substances will be included on the carcinogen list. A spokesman for the Public Health Service, which administers NTP, points out that its listing is based on years of studies of fiberglass, also known as glass wool, and is consistent with a similar listing by the International Agency for Research on Cancer. IARC listed fiberglass as a "possible carcinogen" in 1988. NTP makes its case from laboratory animal studies in which large amounts of glass fibers were surgically implant-
Fiberglass insulation is used in vast majority of U.S. homes.
ed or injected into rodent lungs and abdomens. Tumors resulted. The toxicology program, which is basically a screening process for potential hazards, is required to report such results in its annual reports. The latest list contains seven new compounds (including fiberglass and radon), bringing the total number of compounds either known or anticipated to cause cancer to 180. Makers of fiberglass products, primarily home insulation, object to NTFs listing. The North American Insulation Manufacturers Association (NAIMA), which represents fiberglass makers, points out that human exposure to fiberglass is limited to inhalation. Thus, the association contends "These animal studies using artificial means of exposure do not establish a human health risk." It points out that "research involving extensive human studies and multiple studies in which animals breathed high levels of glass wool show no association between the exposure and cancer." The federal government seems to be downplaying the effect of the listing. In submitting the NTP report to Congress, Department of Health & Human Services Secretary Donna E. Shalala writes, 'The listing of a substance in the annual report does not establish that any substance presents a risk to persons in their daily lives." An NTP listing is only an initial step in the risk assessment process, which is the purview of other federal regulatory and research agencies. Although no federal regulations come into play because of the NTP list-
ing, there are consequences for the $2 billion-a-year fiberglass manufacturing industry. More than a dozen states, among them California, New Jersey, and Pennsylvania, have right-to-know laws that require products sold in those states to be labeled as carcinogens if they appear on the NTP list. However, in this case, NAIMA says that manufacturers voluntarily added a warning label to fiberglass products because of the 1988 IARC carcinogen designation and that no additional label changes will be needed. David Hanson
NIH, NSF issue rules on conflicts of interest Five years after Congress began prodding the government's main biomedical research agency, the National Institutes of Health and the National Science Foundation have simultaneously issued similar regulations governing conflicts of interest. Both agencies give research institutions the responsibility for determining if their researchers' results could be biased by the potential for financial gain and for resolving potential conflicts. The new policies require NIH and NSF grantees to disclose to their institutions any "significant financial interests" that would "reasonably appear to be directly and significantly affected" by NIH- or NSF-funded research. Significant financial interests include con-
sulting fees or honoraria; stocks, stock options, or ownership interests in businesses; and intellectual property rights such as patents and copyrights. The universities must then take steps to manage, reduce, or eliminate their employees' actual or potential conflicts. The institutions can require researchers to publicly disclose their financial interests, modify their research plans, sell the stock in question, or break off relations with firms. NIH and NSF will monitor institutions to make sure they are enforcing the conflict-of-interest policies. The agencies can cut off funding if individual grantees or universities violate the rules. "We think this is the proper way to proceed," says a Congressional staff assistant to Rep. Ron Wyden (D.-Ore.), who in the past has criticized the funding agencies' lack of action. "Enhanced disclosure would have warded off some of the problems we've encountered, particularly in regard to the validity of data submitted in the approval process of new drugs and medical devices." In many cases, NIH grantees have developed these data. NIH's first stab at conflict-of-interest regulations in 1989 would have prohibited NIH-funded investigators, as well as their families and assistants, from owning stock or equity positions in companies that could be affected by the outcome of the research. That proposal was thrown out after the biomedical research community protested vehemently, claiming such tough, inflexible standards would stifle the commercialization of research results. NIH then issued a watered-down version in late 1990 that rapidly sank out of sight. Congress got the ball moving again last summer by inserting into the NIH Revitalization Act a requirement that NIH issue regulations. NSF, meanwhile, proposed in July 1992 that individual investigators disclose their financial holdings directly to the agency. In response to comments from the scientific community, NSF worked with NIH to develop the new uniform set of rules under which the government monitors institutions, not individuals. Both agencies' rules appear in the June 28 Federal Register. NIH's statement (page 33242) is a proposal open to comment from the public until Aug. 29. NSF's (page 33308) is a final notice of policy change. Pamela Zurer JULY 11,1994 C&EN 7
