Chemistry & Diabetes

Unlocking the Promise of LRH-1 for Diabetes and Perhaps Intestinal Inflammation

When we eat, our bodies use a complex network of signals and receptors to organize and process our food. One component of our digestive system is Liver Receptor Homolog 1 (LRH-1). This receptor responds to our meals by altering our metabolism, circadian rhythm, and more. Research previously suggested that the receptor's overexpression could counter the negative effects of diabetes. Now, two Emory researchers, Eric Ortlund, PhD and Nathan Jui, PhD have led the development of a collection of LRH-1 agonist molecules that can be used to activate and modulate the effects of LRH-1 in a controlled manner.

A receptor agonist is a molecule that binds to and activates a receptor. LRH-1 is typically activated by phospholipids, the class of lipids that comprise our cell membranes. "Phospholipids are typically big, greasy molecules that are hard to deliver since our digestive system affects them," Ortlund noted. Ortlund is a professor in biochemistry and one of the leading experts in the study of LRH-1.

"Using information that came from crystallography, we were able to look at the structure of these phospholipids as well as some previous synthetic molecules and design completely new ones," elaborated Jui, an assistant professor in chemistry. "They aren't phospholipids. They don't fall apart and they're highly effective."

Ortlund and Jui worked from a central molecule to develop a library of roughly 250 different agonists. Raj Guddneppanavar, assistant director in Emory's Office of Technology Transfer, explained that "They took a molecule known to bind to LRH-1 and crystalized it – the protein and the molecule together. Using an X-ray to study how the molecule binds, they could modify it to make it bind better. The library of molecules developed is the collection of the different modifications and groups and tests."

The pair have been successful in developing a potent and efficacious agonist. "This molecule has a central core and we've been walking around appendages on that core," explained Ortlund. "We are triaging now, and we have 2-3 lead molecules." The challenge ahead is in retaining those benefits while optimizing certain physical properties of the molecule, such as its molecular weight and solubility.

"We also want to make sure that the enzymes in the liver don't degrade the molecules on a very fast timescale," said Jui.

The duo's work represents a great stride, due in no small part to of the severity of their discovery. "There are labs that avoided the project due to the challenging chemistry around making these things," Ortlund said. Jui's lab would develop the molecules and bring them to Ortlund for testing – first in test tubes, then in cells. The best molecules that emerged at the end of the process would go into mouse trials.

"Organic chemistry is actually very similar to cooking," Jui told me. "It's very easy to make macaroni and cheese and that level of technique is translatable to chemistry. A lot of the methods that people use are based on very reliable, but ultimately very easy chemistry. The central piece of this molecule is on the level of a soufflé, something that's not easy to get to work – and we needed to do it a lot of times."

"We've been able to utilize known chemistry to make a significant portion of our molecules," he continued. "But, we've also begun to divert and invent new ways to make structures that look like this, which allows us to pare out or build up portions of a molecule pretty effectively."

Ortlund and Jui hope their work will lead to the development of a Type 2 Diabetes therapeutic. This form of diabetes is insulin-resistant – it precludes the body's ability take up available insulin. Therapeutics must either improve a patient's insulin response or take a categorically different approach. By modulating the body's metabolism, LRH-1 agonists seem primed to do the latter.

"There's actually a really nice molecule that enhances insulin sensitivity through a different set of nuclear receptors," Ortlund explained. "However, the off-target effect is cancer in the liver, so it can't be pursued."

LRH-1 molecules in the intestine importantly control for cortisol production. Using a model of inflammation induced by chemical damage, Ortlund and Jui found their lead molecules to completely ameliorate inflammation symptoms characteristic of IBS or Crohn's Disease. One challenge ahead will be to prove that the agonist molecules are safe, particularly as their primary targets are chronic conditions.

"So far, at our highest doses, we haven't seen any overt, obvious toxicity," Ortlund stated. "With the highest doses given to guinea pigs and mice, they're not showing stress and they're not dying, so that's really good and hopefully true for humans."

The duo has started a collaboration with Thermo Fisher to receive primary human hepatocytes, otherwise known as liver cells, for testing purposes. "When people go into the clinic and get a biopsy, those cells can be taken and cultured and those are real human cells," Ortlund explained. "We add our modulators to those human liver cells and the good thing is they act like they're a liver because they're still from that environment and make all the right enzymes." The next step will be to make these liver cells "sick" and attempt to cure their sickness, and then to replicate the process with intestinal cells.

Otherwise, Ortlund and Jui foresee future possibilities in the development of LRH-1 antagonists, which, contrary to agonists, bind to the receptor and suppress its response. The hope would be to develop therapeutics for certain forms of cancer such as breast cancer, where LRH-1 controls estrogen production.

"Their targets are broadly covered by their lead compounds," Guddneppanavar described, "meaning their work can be applied to the development of various individual drugs."

While the direct precision of their agonists' therapeutic effects is central to the noteworthiness of their discoveries, Ortlund finds motivation in uncovering the tensions that still challenge their work – "Hitting one specific target is clean, but the reality is maybe broadly affecting pathways gives you a more potent biological response. You have to balance the power of that versus really knowing what the molecule is doing at a target."

Jui remains invested in the process of drug design and the particular form of problem-solving it begets – "In synthesis, you have the opportunity to build things and there are so many different ways to go about doing that specific task that there's a really deep, awesome aesthetic piece of it." The collaboration's pairing of vision and technique already carries novel insights and as possibilities emerge for research paths ahead, the two are braced to further their understanding of the molecular pairing that comprises their work.

Techid: 17001

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