a $15,000 annual sustaining grant that is administered by the American Chemical Society. The pharmaceutical firm Syntex Corp. has been giving $10,000 annually for a program that this year is up for renewal. The United Nations Population Fund supports the fertility regulation program w i t h an annual $90,000 grant. An additional $25,000 for screening of chemotherapeutic agents comes from the European Community every year. A $100,000 grant from the Mellon Foundation for the testing on rabbits of antifertility drugs is now winding down. But, says Maybury, current support is merely a drop in the bucket compared with the two basic needs: science for development, and the nurturing of university-based chemical talent in Africa, Latin America, and Asia. He concedes that considerable sums of money do go to the Third World, especially in the form of World Bank loans. But almost none
of that money actually goes toward scientific research or the screening of chemicals for health needs. Drug companies fund their own screening programs, but often the knowledge gained is too proprietary for the common good. Also, the IOCD program helps Third World chemists remain scientists by giving them chemical work. Too often these scientists return home after being educated abroad to find no technical work. If the $15 membership plan succeeds, says Maybury, the money will go to the funding of the various working groups in the Third World, such as workshops on plant bioassays. "It will increase the number of Third World chemists in the working group orbits," he says. For example, new money would be used to fund the screening and testing of various antimalarial compounds designed by chemist Sidney Archer of Rensselaer Polytechnic Institute. Wil Lepkowski
Circular DNA excels at nucleic acid recognition Eric T. Kool has a novel idea: Circular DNA oligonucleotides are better than conventional ribbons of DNA at recognizing nucleic acid sequences. He has discovered that these DNA circles bind nucleic acid sequences "several orders of magnitude more strongly" than standard linear oligomers do, and they are more selective for the correct sequence. "To our knowledge, these are the strongest known intermolecular nucleic acid complexes under physiological conditions," says Kool, an assistant professor of chemistry at the University of Rochester, N.Y. "Although circular polynucleotides are abundant in nature," Kool notes, few studies have focused on small, synthetic DNA circles. And no one else, as far as he knows, has addressed their potential in molecular recognition, he adds. Since joining the faculty of Rochester a year ago, Kool and technical associate Gautam Prakash have been synthesizing 34-nucleotide loops and studying how they bind complementary DNA or RNA strands. The loop, it turns out, forms hydrogen bonds to the strand on two sides, forming a triple helical complex. A loop con-
taining long stretches of thymines (T) and cytosines (C), for example, will bind to a strand of adenines (A) and guanines (G) so that T-A-T and C-G-C base triads are formed. On one side of the loop, the hydrogen bonding pattern is of the traditional Watson-Crick type found in normal DNA. On the other side of
DNA circle binds to linear DNA strand
Both sides of the circle (color) form hydrogen bonds to a segment of the target strand, forming a triple helical structure
the loop, the bonding pattern is of the nontraditional (and weaker) Hoogsteen type, which requires that cytosine be protonated. In other words, both sides of each purine base (A or G) are complexed to the DNA circle—on one side, at the purine's usual binding sites, and on the other side, at its atypical binding sites. In this way, Kool notes, pyrimidine-rich circles can be designed to recognize purine sequences in single-stranded polynucleotides. Kool has performed experiments to assess how well such a DNA circle discriminates between a complementary nucleic acid sequence and one that results in a mispairing of bases. In all cases studied, he finds that the cyclic oligomer "shows greater selectivity for its correctly matched sequence than does the standard linear oligomer." In one series of experiments, for example, the circular DNA was 10- to 100-fold more selective than the linear oligomer, Kool says. One paper on this work has just appeared [/. Am. Chem. Soc, 113, 6265 (1991)] and another will be published later this month. DNA circles may also perform better than linear oligomers at distinguishing between DNA and RNA sequences, Kool says. RNA contains uracil (U) instead of T. This difference in the bases would be picked up more readily by a circle because the circle would also read the "back side" of U and notice that it, unlike T, has no methyl group jutting out. Cyclic oligomers have potential applications in the design of DNAbased drugs that target nucleic acid sequences, say, in messenger RNA or viral RNA. Researchers at a number of labs, for example, have been trying to use antisense oligonucleotides—strands complementary to RNA's "sense" sequence—to specifically inhibit gene expression. Linear antisense oligomers have been shown to have some antiviral activity, Kool says. Circular DNA, with its greater binding strength and specificity, may lead to better antisense agents, he believes. And, as another scientist recently noted, "circular oligonucleotides are resistant to exonuclease digestion, nicely avoiding one of the serious shortcomings of natural antisense oligonucleotides." Ron Dagani August 12, 1991 C&EN
29
