Researchers discover llama-derived nanobody can be potential therapy for hard-to-treat diseases

July 9, 2018, Case Western Reserve University
Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor. Credit: Nature Communications (2018). DOI: 10.1038/s41467-018-04432-0

Researchers from Case Western Reserve University School of Medicine have found a nanobody that holds promise to advance targeted therapies for a number of neurological diseases and cancer.

In a recent study published in Nature Communications, Sahil Gulati, of the Department of Pharmacology at Case Western Reserve School of Medicine, and colleagues identified a nanobody derived from a llama that targets signaling of G protein-coupled receptors (GPCRs), a large family of receptors involved with transmitting signals in cells.

The llama-derived nanobody specifically targets a component of G protein known as G beta-gamma—the part that binds and efficiently activates several other signaling proteins. These proteins, once activated, have been linked to several types of cancers, neurological disorders and drug addiction.

The nanobody binds G beta-gamma tightly and prevents it from activating these signaling proteins. While blocking the G beta-gamma signaling, the nanobody has no effect on essential GPCR signaling events that are required for normal cellular function.

A drawback of current therapeutic approaches targeting GPCRs is that small drug molecules are not very selective, and activate additional signals other than the intended target, causing unwanted side effects.

"You would like the drug to bind one GPCR, but it binds non-specifically to other GPCRs causing unwanted and sometimes damaging side effects," said Gulati. "That's the problem with small molecule drugs on the market today."

In addition, most small molecule and antibody-based treatments are made to target specific GPCRs. However, there are almost 1,000 different GPCRs in humans, and thereby 1,000 separate drug development pipelines will be required to target each one of them.

"This is an extremely expensive scenario and it will take decades of research and development to find therapies to target each GPCR," Gulati added.

GPCRs are important targets for the pharmaceutical industry. As of November 2017, roughly 20 percent of FDA-approved medications target GPCRs, including medications for asthma, pain, osteoporosis and .

Nanobodies are derived from specialized antibodies found only in sharks and camels (llamas are part of the camelidae family). Gulati explained that nanobodies are antibody fragments that are cheap to produce and efficient to deliver as a therapy. They are on their way to being a viable class of therapeutics against several hard-to-treat diseases.

Gulati and his group of scientists targeted GPCR signaling in an unconventional manner. They have targeted G proteins and not GPCRs themselves. G proteins are the immediate downstream players in GPCR signaling pathways. Targeting G proteins can provide control on several GPCRs and might also avoid undesired cellular events, Gulati said.

"This approach might potentially be a silver bullet for treating several medical conditions with GPCRs as key targets," Gulati said. "The study serves as the first example where a nanobody has been shown to alter GPCR signaling at the G level by inhibiting G beta-gamma signaling. This will enhance the potential of nanobodies to treat various neurological conditions and cancer progression."

Use of nanobodies will likely grow as research shows they are an important tool for modulating cellular signals.

Explore further: CryoEM study captures opioid signaling in the act

More information: Sahil Gulati et al, Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor, Nature Communications (2018). DOI: 10.1038/s41467-018-04432-0

Related Stories

CryoEM study captures opioid signaling in the act

June 22, 2018

Opioid drugs like morphine and fentanyl are a mainstay of modern pain medicine. But they also cause constipation, are highly addictive, and can lead to fatal respiratory failure if taken at too high a dose. Scientists have ...

Heart disease severity may depend on nitric oxide levels

May 14, 2018

The most common heart medications may get an assist from nitric oxide circulating in the body, according to a new study out of Case Western Reserve University School of Medicine. Researchers showed that nitric oxide may help ...

Research could minimize unwanted side effects in new drugs

May 3, 2018

Opioids relieve pain, but can cause respiratory failure and death through overdosing. Antipsychotic drugs can help people cope with mental illnesses, but muscle spasms can be a debilitating side effect. What if we could design ...

Cryo-EM reveals interaction between major drug targets

June 13, 2018

For the first time, scientists have visualized the interaction between two critical components of the body's vast cellular communication network, a discovery that could lead to more effective medications with fewer side effects ...

Recommended for you

Graphene on the way to superconductivity

November 9, 2018

Scientists at HZB have found evidence that double layers of graphene have a property that may let them conduct current completely without resistance. They probed the band structure at BESSY II with extremely high resolution ...

Directivity to improve optical devices

November 9, 2018

A team of researchers from the Dutch institute AMOLF, Western University (Canada), and the University of Texas (United States of America) recently demonstrated the use of algorithmic design to create a new type of nanophotonic ...

Graphene takes a step toward renewable fuel

November 8, 2018

Using the energy from the sun and graphene applied to the surface of cubic silicon carbide, researchers at Linköping University, Sweden, are working to develop a method to convert water and carbon dioxide to the renewable ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.