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Redesigned jellyfish gene helps screen for HIV drugs

By David Robson, 09-Apr-2008

Related topics: Applications, Lab Consumables, Reagents (protein, genomic, PCR, cell-culture), Screening (HSC / HTS)

Geneart has been awarded a patent for its drug screening technology, which could aid the discovery of a new type of antiviral drug for HIV and other viruses.

The cell-based assay makes use of a re-engineered jellyfish gene, which produces a fluorescent product when it successfully copies the HIV virus's behaviour.

The assay will allow scientists to investigate drugs that could target one of the virus's key processes. Once the virus has infected a human white blood cell, it needs to move its genetic information, in the form of messenger RNA, from the nucleus to the cytoplasm of the cell, in order to produce protein products and to replicate itself.

The transferral process involves different cellular and viral proteins which bind to the mRNA to move it from one part of the cell to the other. Human cells also transfer mRNA from the nucleus to the cytoplasm, but the HIV virus mRNA in an infected cell uses very different nuclear export pathway to those mRNAs normally used by human cells.

Scientists hope that drugs which target this export mechanism could prevent the HIV virus from replicating within the human body while leaving the human pathways in healthy cells untouched.

However, to find these drugs, scientists need to determine whether a chemical does indeed prevent this process from occurring. Previous techniques would involve studying the enzymes and proteins produced by the virus. Geneart's technique, however, means that scientists can now identify new antiviral drugs which for the first time would target pathways transferring genetic material .

"We have built a cell-based assay that focusses on the mRNA export itself," says Marcus Graf from Geneart, who helped invent the system. "I think it's quite unique."

To do this, Graf and his colleagues re-engineered a gene from the jellyfish, which is normally responsible for a fluorescent green protein, so that it would transfer its mRNA through pathways similar to those used by the HIV virus.

Once the genetic material has been transferred to the cytoplasm, the information encoded in the mRNA triggers the production of the fluorescent green protein, which causes the cell to light up. However, if the pathway is blocked and the mRNA could not escape from the nucleus, the cell would not light up, and the change can be detected using optical equipment.

It is likely that if a drug effectively blocks this pathway and prevents the synthetic HIV-like gene from transferring its material in this way, then it would also block the HIV virus from transferring its genetic material too.

Redesigning the jellyfish gene was no easy task - the team needed to use powerful scientific software to change the DNA sequence so that the mRNA would use the virus's protein pathways, while still being capable of producing the fluorescent protein

"In the end, the gene was heavily changed. This was only possible using rational gene design and de novo synthesis technology. On top of this, we can now apply this gene reprogramming not only on a jellyfish gene, but to any suitable reporter gene!" said Graf.

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