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Earlier in the week, we reported on a case of rational drug design: given the structure of a protein, scientists were able to pick a molecule with a structure that stuck to the protein. But this sort of rational approach really only works if you have a structure and know where the key parts of it are. Unfortunately, that is a fairly rare situation. But some new results that were published recently suggest that we needn't have to wait for structural data to come in to design a drug: evolutionary processes work great even when we're in the dark. In this case, the processes were used to evolve a molecule that dramatically extended the life span of an experimental organism. 老域名购买

The basic concept of the approach is to start with an entirely random pool of molecules and then subject them to several rounds of selection based on binding to a target protein. Those that are still around after all the selection—the "fittest"—should include everything that specifically stick to your protein of interest. This sort of technique has been used successfully by a number of labs.

The research team involved combined that logic with a neat technique that dates from 1997, one that allows them to essentially select for a molecule and the instructions for making it at the same time. The technique relies on creating random pools of RNAs that can be made into short proteins. These RNAs are chemically linked to an antibiotic and then given to purified ribosomes, which translate them into proteins.

The antibiotic being used is puromycin, which has a key mechanism of action: it normally sneaks into the ribosome and gets attached to the end of the proteins that are being made, stopping their manufacture. In this case, it gets attached to the protein being made from the RNA it is fastened to, thus linking the RNA to the protein it codes for. When these proteins are sent through the selection process, the ones that survive come linked to the RNA that includes the instructions for making them.

In this case, the authors chose a compelling item to target with this technique: a receptor called Methuselah, which previous experiments had shown was involved in regulating the life span of the fruit fly Drosophila. The researchers put their pool of protein/RNA hybrids through eight rounds of selection for binding to the Methuselah protein and then identified the RNAs that encoded the most efficient binding proteins. They then tested these to find the ones that would compete with the signals that the receptor normally binds, reasoning that these would be the most likely to block signaling.

To test the effectiveness, the researchers converted the sequence of the RNA into DNA, and inserted it into the Drosophila genome. Expression of the evolved protein extended the mean lifespan of flies by 38 percent, and the maximum lifespan by 26 percent. In short, the researchers evolved an anti-aging peptide.

For the curious, Methuselah doesn't seem to have a direct equivalent outside of the fly world, so these new proteins aren't going to be showing up in pharmacies any time soon. But the techniques involved look to be powerful ones, and similar approaches may be generating something useful before too long.


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