Chemical & Engineering News

February 24, 1997


Copyright © 1997 by the American Chemical Society

'Evolution' used to isolate high-affinity ligands

A method that uses the concept of test-tube "evolution" to generate ligands for compounds of chemical or biological interest was reported earlier this month by medicinal chemistry professor Alexey V. Eliseev and postdoctoral associate Marina I. Nelen of the State University of New York, Buffalo [ J. Am. Chem. Soc., 119, 1147 (1997)].

Eliseev's technique "bears the potential to become a system in which Darwinian evolution-type principles are applied, which would be a milestone in small-molecule combinatorial chemistry," comments biochemistry professor Michael Famulok at the Genzentrum of Ludwig Maximilians University, Munich, Germany. Famulok specialized in the in vitro selection of nucleic acids from combinatorial libraries.

The paper describes the enrichment of a dicarboxylate that bound with highest affinity to a target. The dicarboxylate is selected from a "combinatorial library" of three dicarboxylate isomers that interconvert under ultraviolet light. After the highest affinity dicarboxylate (the cis,cis isomer) is removed from the mixture by affinity chromatography, it is regenerated by isomerization of the other two (cis,trans and trans,trans). Eliseev and Nelen refer to this regeneration process as "mutation". Iterative removal of the cis,cis isomer from the mixture and its regeneration from the other two isomers results in its enrichment.

One advantage of the technique, comments Famulok, is that it identifies an active component simply by enriching it in iterative selection and amplification cycles--regardless of how little of that component was initially present. Although this has been done previously for nucleic acid libraries--using the polymerase chain reaction (PCR) for amplification--"the fact that Eliseev has done something similar now with a three-compound 'library' of small organic molecules is remarkable," says Famulok.

However, he points out that it is debatable whether the term "mutation" is appropriate to describe the process. "Mutation" implies that the diversity of a mixture is increased, whereas in Eliseev's system three isomers are simply interconverted.

But Eliseev replies that the pool used in his experiment did initially contain only a single compound (the trans,trans isomer), and that this isomer "mutated" to form the other two. Eliseev currently is exploring extending the technique to systems with other types of components, such as imines that could be reversibly formed from a polyaldehyde and a set of amines.

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