Along the upper reaches of cell signaling loom the G protein-coupled receptors (GPCRs). From these serpentine structures descend pathways that diverge toward varied signaling outcomes, not all of which are desirable. For example, signaling cascades triggered by small-molecule drugs may lead to several types of cancer, neurological disorders, and drug addiction. Yet where small-molecule drugs may slip up, a sure-footed nanobody may stick to the right path, advancing targeted therapies.
The nanobody is derived from a llama. Discovered by scientists based at Case Western Reserve University, the nanobody targets a component of G protein known as G beta-gamma—the part that binds and efficiently activates several other signaling proteins. This kind of binding has potential therapeutic applications. Even better, with the llama-derived nanobody, this kind of binding is not accompanied by other kinds of binding that might bring about adverse side effects.
Specifically, drugs based on the llama-derived nanobody might head off disease-associated signaling while preserving signaling that is required for normal cellular function.
Details about the nanobody appeared in a study (“Targeting G protein-coupled receptor signaling at the G protein level with a selective nanobody inhibitor”) that appeared recently in Nature Communications. This study explains that the nanobody binds tightly to G beta-gamma (Gβγ), but not to another part of the GPCR, G alpha (Gα).
“Here we report a llama-derived nanobody (Nb5) that binds tightly to the Gβγ dimer,” the article’s authors wrote. “Nb5 responds to all combinations of β-subtypes and γ-subtypes and competes with other Gβγ-regulatory proteins for a common binding site on the Gβγ dimer. Despite its inhibitory effect on Gβγ-mediated signaling, Nb5 has no effect on Gαq-mediated and Gαs-mediated signaling events in living cells.”
"You would like the drug to bind one GPCR, but it binds non-specifically to other GPCRs causing unwanted and sometimes damaging side effects," says Sahil Gulati, a researcher in the department of pharmacology at Case Western Reserve School of Medicine. "That's the problem with small molecule drugs on the market today."
Most small molecule and antibody-based treatments are made to target specific GPCRs. However, there are almost 1,000 different GPCRs in humans, and therefore 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 adds.
GPCRs are important targets for the pharmaceutical industry. As of November 2017, roughly 20% of FDA-approved medications target GPCRs, including medications for asthma, pain, osteoporosis, and high blood pressure.
Nanobodies are derived from specialized antibodies found only in sharks and camels (llamas are part of the Camelidae family). Gulati explains 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 says.
"This approach might potentially be a silver bullet for treating several medical conditions with GPCRs as key targets," Gulati says. "The study serves as the first example where a nanobody has been shown to alter GPCR signaling at the G protein 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.