New tools to build synthetic hormonal pathways

The late Richard Feynman once said, “What I cannot create, I do not understand.” Although this principle is well known to physicists and engineers, it has only recently become the mantra of a cadre of scientists seeking to build new biological pathways in living animals. In this issue of PNAS, Armbruster et al. (1) report an important new tool for pharmacologists seeking to build designer G protein-coupled receptors (GPCRs) to control signaling pathways. This family of receptors has been fine-tuned over millions of years to sense molecules ranging from yeast pheromones to neurotransmitters. Nature has evolved hundreds of human GPCRs, and the pharmaceutical industry spends billions of dollars to develop GPCR drugs that frequently top the list of best-selling medicines. However, despite intense studies, many mysteries remain about how GPCRs function in vivo. Although GPCR drugs and gene knockouts have taught us a great deal, some lessons may only be learned by building new GPCR signaling pathways in living animals.

The first attempt at making a designer GPCR was led by Catherine Strader (2), who developed a series of compounds to selectively activate a mutant version of the β-adrenergic receptor that was unresponsive to its natural hormone. Unfortunately, this elegant work only yielded compounds with millimolar affinities, with unknown pharmacokinetics, making in vivo work impractical.

Later, my laboratory devised a series of RASSLs (receptors activated solely by a synthetic ligand) with nanomolar agonists, making in vivo use possible for the first time (3). The key to making these first RASSLs was to take advantage of potent preexisting synthetic drugs, such as kappa opioid agonists (e.g., spiradoline), that had been developed by the pharmaceutical industry as potential analgesics. A RASSL could be made by introducing mutations that abrogated signaling via the natural peptide ligands yet …

*E-mail: bconklin{at}gladstone.ucsf.edu