“Near drug” finally meets its match

LG335.

Thanks to the Human Genome Project, thousands of previously unidentified genes and proteins are waiting to be explored. To simplify this very complex task, methods are needed to target individual proteins within the cell’s vast functional network for investigation. Nuclear hormone receptors are a superfamily of ligand-inducible transcription factors that may be useful tools for this purpose. The receptors activate gene expression in response to being paired with small-molecule ligands. In addition, their ligand and DNA binding domains function independently, so the ligand domain can be grafted onto DNA binding sites, allowing for the control of a wide range of possible genes. But for this approach to be effective for targeted study, a ligand–receptor pair must be orthogonal, and, therefore, unresponsive, to the native receptors and native small molecules of the cell under study.

Recently, scientists have shown that receptors can be easily modified to achieve orthogonality. However, the synthesis of ligands suitable for this purpose has proved more difficult and time-consuming.

But this may no longer be the case, according to work carried out by Donald Doyle and colleagues at the Georgia Institute of Technology (Atlanta) and the University of Texas (Dallas) (J. Amer. Chem. Soc. 2001, 123 (46), 11367–11371). The researchers have engineered an orthogonal ligand–receptor pair by using a mutated receptor and ligands, termed “near drugs”, that were rejected from retinoid X receptor (RXR) agonist screening experiments but are structurally similar to the approved compounds. They reasoned that slight variations in the amino acid residues of the RXR ligand binding site might encourage a “near drug” to induce transcription. Doyle and his group compared the abilities of two RXR agonists, LG69 and LG153, with those of their inactive analogues, LG94, LG75, and LG335, to activate transcription in a series of mutant and wild-type RXRs. Significantly, using only 19 mutant receptors, the scientists successfully engineered an orthogonal pair between the “near drug” LG335 and a triple variant of RXR.

A major benefit of this approach, says Doyle, is that the ligands “are already synthesized and are not something that have to be pursued as a separate project.” He adds, “Since they are similar to approved drugs, they are likely to have similar pharmacokinetics and to pass all the other hurdles that successful drugs have to pass.” These factors combined could likely add up to the accelerated development of new protein probes and potential gene therapies.

Currently, the researchers are applying their “near drug” strategy to other hormone receptors. They hope to rapidly identify 12–20 new orthogonal ligand–receptor pairs.

—JENNIFER BARBOUR McKELLAR

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