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Encapsulated in cell surface membranes, GPCRs trigger metabolic changes in response to binding by hormones, neurotransmitters and drugs. Nearly all physiological processes depend on these

receptors, but when Robert Lefkowitz first joined the faculty at Duke University in 1973, their existence was still in doubt. For many scientists, “GPCRs were a vague concept with no basis

in physical reality,” Lefkowitz says. Eventually, Lefkowitz proved the doubters wrong. His success leading the first team to ever purify and clone a GPCR — the β2−adrenergic receptor —

produced a Nobel Prize that the Duke professor shared in 2012 with Brian Kobilka, now at Stanford, who solved the receptor’s crystal structure. Targets for most GPCR drugs — which include

antihistamines, beta-blockers, psychiatric medications and other common therapies — are still concentrated in just a few receptor subfamilies. But advances by Lefkowitz and other scientists

are unleashing fresh opportunities. Lefkowitz recently co-founded Septerna, a biotechnology company working to bring previously undruggable GPCRs into the clinic. The company arose out of

initial discussions in 2019 between Lefkowitz and Jeffrey Finer, a partner at Third Rock Ventures in Boston. Third Rock was interested in modernizing GPCR drug discovery, and as soon as

Finer began scouting for global experts in the field, Lefkowitz popped up on the radar. The researcher and his students were developing advanced computational and structural methods to

identify GPCR binding sites. And they had recently identified a small-molecule negative allosteric modulator for the β2−adrenergic receptor in a DNA-encoded library. “We found this

particular achievement very inspiring,” Finer says. “The β2-adrenergic receptor had already yielded several approved drugs, including beta-blockers and beta-agonists. But no one had ever

discovered allosteric modulators for that receptor before.” Finer proposed that Third Rock and Lefkowitz join forces. The Duke team was already mulling over the idea of forming a company to

pursue opportunities with GPCRs, “and it was fortuitous that Finer reached out to us,” Lefkowitz says.. The Duke team spent the following months figuring out ways to speed up high-throughput

screening and structure-based GPCR drug design. Lefkowitz had developed methods for isolating receptors in functional forms, but commercial applications depended on industrializing those

processes “so that what takes months or years in academic settings could be accomplished in days or weeks,” Finer says. Third Rock recruited two more co-founders, both from Monash University

in Melbourne, Australia: Arthur Christopoulos, who specializes in GPCR allosteric modulation, and Patrick Sexton, an expert in using cryo-electron microscopy (cryo-EM) to elucidate GPCR

structures and dynamics. Meanwhile, the growing team pressed forward on key priorities, one being to generate quick high-resolution structures with cryo-EM and another to optimize lab

methods with DNA-encoded libraries so that potential drug candidates could be screened by the billions. The operational platform resulting from efforts, which Septerna calls the Native

Complex, recapitulates a GPCR’s natural structure, function and dynamics in a cell-free system. “Coupled receptors are reconstituted with a ligand and contained within a miniature artificial

membrane that completely mimics that natural cell environment,” Finer explains. In other words, Septerna had developed a way to put pure receptors into test tubes while keeping them fully

active. “What really made this possible were new surfactants and methods to extract GPCRs from cell membranes,” says Aashish Manglik, a pharmaceutical chemist at the University of

California, San Francisco. “Now we have functional GCPRs to play with, and that wasn’t possible until about five or six years ago,” says Lefkowitz. Septerna was soon churning out

high-resolution three-dimensional GPCR structures at a rate of one a week, “which, for drug-discovery chemists, is a real game changer,” Finer says. Septerna finally launched in January 2022

after securing $100 million in Series A funding. A series B round completed in June 2023 hauled in an $150 million more to support the company’s growing pipeline of oral small-molecule drug

candidates. Finer now serves as the Septerna’s CEO. Bryan Roth, a pharmacologist who studies GPCRs at the University of North Carolina School of Medicine, says the company’s platform is

particularly well-suited to identifying allosteric modulators, which can allow lower dosing and create opportunities to fine-tune the activity of a target organ. Nearly all approved drugs on

the market today are orthosteric, meaning they compete with natural ligands for an active binding site. By contrast, allosteric compounds can bind to a range of different sites on a single

receptor. Positive allosteric modulators increase the activity of an endogenous ligand while negative modulators diminish the ligand’s activity, in some cases completely. However, finding

these compounds poses complex technical challenges and requires the sort of expertise that, Roth says, other drug companies lost when GPCRs fell out of fashion years ago. “One of the

remarkable things about Septerna is that they really cornered the global market for people trained in GPCRs and allosteric concepts,” he says. The company now has just over 50 employees.

Septerna’s pipeline is focused on endocrine, inflammatory and metabolic diseases. And one of its lead compounds is a negative allostatic modulator for treating Graves’ disease, which occurs

when stimulatory autoantibodies target the human thyrotropin receptor. The resulting hyperthyroidism damages organs. And since these sorts of GPCRs also appear on fibroblasts behind the eye,

many patients develop Graves’ ophthalmopathy, a sight-threatening disease. According to Finer, patients typically generate a range of different antibodies against the receptor. But where

orthosteric antagonists can only target one antibody at a time, a negative allosteric modulator can work against any autoactivating antibody and thereby “treat all Graves’ and Graves’ eye

disease patients instead of just a subset of them.” Yet another high-hanging fruit set in Septerna’s sights is biased signaling. This approach stems from research in Lefkowitz’s lab showing

that some GPCR-acting compounds signal either through G protein or _β__-_arrestin pathways. Compounds that signal preferentially via one pathway or the other are called biased ligands.

“There’s a lot of interest in the industry to develop these sorts of biased molecules,” Lefkowitz says. “Biased ligands are often more specific, have less side effects, and can at least

theoretically be safer than other drugs.” But how does one discover ligands that are biased in either direction? Here again, Lefkowitz says, the Native Complex platform comes into play.

Purified receptors can be complexed to “either the G protein or a _β__-_arrestin, and if you use that as your target, you will be able to isolate a biased ligand,” Lefkowitz says. “That’s

because the receptor will then be in the conformational shape that likes to bind to one of these proteins or the other.” In Roth’s view, GPCR research today is similar to where cancer small

molecules were 15 years ago. “There’s a level of interest in GPCRs now that I haven’t seen for decades,” he says. “I’ve been contacted by a lot of other venture groups and startups in the

area of GPCR drug discovery, but Septerna is really the biggest force out there. They’re moving at warp speed. It’s really quite astounding.” _Charles Schmidt_ _Portland, ME, USA._