GPCRs are the targets for around one third of all approved drugs1. Yet such medicines act on only a handful of the 800+ known GPCRs. A wave of biomedical progress in the early 21st century thrust these receptors into the spotlight, but many proved intractable for drugmakers and fell by the wayside.
“What makes them such attractive targets is their position right at the top of every cell’s communication pathway, and their involvement in pretty much every disease you can think of,” says Fiona Marshall, president of biomedical research at the Novartis Institute for Biomedical Research.
The ubiquitous presence and transmembrane location of GPCRs presented challenges, however. First, with obtaining a molecular structure around which an optimal drug could be designed, and second, avoiding off-target effects caused by hitting multiple GPCRs.
Now, thanks to advances in structural biology, several of which earned Nobel prizes, a new generation of more selective GPCR-targeted drugs is within reach. Not surprisingly, this has led to renewed interest from the drug industry: pharmaceutical companies, needing to replenish their pipelines; innovative biotechs using GPCR structure-based approaches to create differentiated and potentially first- or best-in-class drug candidates; and investors, who believe there are significant financial rewards from backing these businesses.
It would be fair to say that the GPCR business is big news again.
A structural revolution
One of the roots of this GPCR story can be traced back to advice given in 1970 to a physicist named Richard Henderson, who was working on bacterial rhodopsin at the MRC Laboratory of Molecular Biology in Cambridge. Henderson recalls that a colleague suggested he “move away from this boring bacterial protein”.
He broadened to studying human membrane proteins instead: “But it took ten years to even generate a crystal for X-ray crystallography, and a further seven to get a structure.”
The breakthrough in GPCR stability and crystallization came in 2005. This led Henderson and his colleague Chris Tate to co-found Heptares Therapeutics in 2007, along with Malcolm Weir who became CEO, based on the proprietary technology they developed.
Marshall, who had already spent much of her career working on GPCR drug discovery, joined the firm as a co-founder and CSO. “Those first few years we were refining the technology and we made some big steps forward.”
Other labs were also exploring ways to stabilize GPCRs, including the academic groups of Brian Kobilka, Ray Stevens and Ehud Landau. “These technologies came together and led to an explosion in crystal structures,” recalls Marshall.
Around 2014, Henderson worked out a way to combine thousands of electron cryomicroscopy (cryo-EM) pictures of single molecules to reveal complicated structures — work that earned him a share of the Nobel Prize in Chemistry in 2017. “It turned out to be especially productive for solving the structure of G-proteins coupled to their receptors,” he says.
Expanding markets for GPCRs
As well as the leap from X-ray crystallography to cryo-EM, “emerging biology was showing the importance of GPCRs across an increasing number of diseases,” says Marshall.
The range of diseases that involve GPCRs is extensive, including asthma, pain, schizophrenia, Parkinson’s disease, cancer, depression, hypertension and incontinence.
One current industry success story are the injectable peptides for diabetes and obesity, which target the GPCR for glucagon-like peptide-1 (GLP-1)2. In the third quarter of 2024 alone, semaglutide achieved sales of US$6.9 billion for Novo Nordisk, while tirzepatide revenue was US$4.4 billion for Eli Lilly. Heptares published the first crystal structure of the GLP-1 receptor in 20173, opening the possibility of structure-based drug design for this target.
Another area finally showing promise are the muscarinic receptors in neuropsychiatric disorders4. Drug developers have been trying to crack these receptors for decades, but the similarity between the five subtypes was a challenge.
“The M4 subtype was a risky one for us to pick, as not everybody believed in it,” recalls Marshall. Off-target effects killed most muscarinic agonist programmes. However, one strategy to offset the lack of selectivity was to combine a non-selective agonist with a peripheral antagonist, resulting in FDA approval for schizophrenia in 20245. Another approach taken by several companies, thanks in part to structural insights, is to develop selective M1 and/or M4 agonists for schizophrenia and other neurological diseases.
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