The birth of combinatorial chemistry in the early nineties promised to revolutionize this laborious process by offering a way to synthesize trillions of compounds at a time. These test tube techniques have been refined to "evolve" collections of as many as a quadrillion different proteins or nucleic acids to bind a molecular target. These techniques are called molecular breeding, because like traditional livestock and crop breeding techniques, they combine sets of genotypes over generations to produce a desired phenotype. Molecular breeding has been restricted to selecting protein or nucleic acid molecules, which have not always been the best lead compounds for drugs. Conventional synthetic organic chemistry, which has traditionally been a better source of candidate drugs, has not been amenable to this type of high throughput molecular breeding.
But this bottleneck has potentially been overcome and is described in a series of three articles by David Halpin et al. in this issue of PLoS Biology. By inventing a genetic code that acts as a blueprint for synthetic molecules, the authors show how chemical collections of nonbiological origin can be evolved. In the first article, Halpin et al. present a method for overcoming the technical challenge of using DNA to direct the chemical assembly of molecules. In the second, they demonstrate how the method works and test its efficacy by creating a synthetic library of peptides (protein fragments) and then showing that they can find the "peptide in a haystack" by identifying a molecule known to bind a particular antibody. The third paper shows how the method can support a variety of chemistry applications that could potentially synthesize all sorts of nonbiological "species." Such compounds, the authors point out, can be used for drug discovery or as molecular tools that offer researchers novel ways to disrupt cellular processes and open new windows into cell biology. While medicine has long had to cope with the evolution of drug-resistant pathogens, it may now be possible to fight fire with fire.
citation:Halpin DR, Harbury PB (2004) DNA display I. Sequenceencoded routing of DNA populations. PLoS Biol 2(7):e173.
DOI: 10.1371/journal.pbio.0020173
Halpin DR, Harbury PB (2004) DNA display II. Genetic manipulation of combinatorial chemistry libraries for smallmolecule evolution. PLoS Biol 2(7):e174.
DOI: 10.1371/journal.pbio.0020174
Halpin DR, Lee JA, Wrenn SJ, Harbury PB (2004) DNA display III. Solidphase organic synthesis on unprotected DNA. PLoS Biol 2(7)e175.
DOI: 10.1371/journal.pbio.0020175
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http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371%2Fjournal.pbio.0020174
http://www.plosbiology.org/plosonline/?request=get-document&doi=10.1371%2Fjournal.pbio.0020175
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