New gold-nanoparticle probes for target recognizable proof of bioactive small molecules

Overview

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• Source: Tokyo University of Agriculture and Technology


• Date: 02 Feb,2021

The development of pharmaceutical treatments is difficult — clinicians and researchers know a certain drug can regulate particular functions, but they may not understand how it actually works.

Bioactive small molecules are chemical compounds, such as pharmaceuticals, that can be readily delivered to and interact with a human body’s cells. By binding to specific proteins, these molecules can rewire a biological process to stop or enhance whatever the first function was. For example, the bioactive small molecules in an anticancer agent will bind with a protein in cancer cells to inhibit their uncontrolled growth. They could even to trick the cancer cells to programmed cell death.

The challenge is that it’s not always clear which proteins are being targeted or whether there are additional proteins targeted that may potentially cause undesirable side effects. Using a technology called photoaffinity labeling, researchers can shine light on target proteins and instantaneously tag them, identifying and capturing them. But, photoaffinity labeling requires extensive time and resources to create the specific tag, ensure it’s attached to the perfect target in the cell and then purify the labeled target protein.

“Photoaffinity labeling is a powerful approach for the discovery of small molecule-target proteins,” Sakurai said. “However, its routine use has been hampered by several problems, including wasteful protein tagging and subsequent purification and technical issues of creating bioactive small molecules into appropriate probes.”

We set out to develop a new gold nanoparticle-based method for target identification of bioactive small molecules that streamlines the current laborious steps so that we can rapidly find out how these molecules work.”

Kaori Sakurai, Associate Professor, Department of Biotechnology and Life Science, TUAT

Sakurai’s team formerly supplied a solution to the first issue by employing a gold nanoparticle as modular scaffolding where a specific probe can be designed. In the recent paper, they concentrated on developing a one-step preparation procedure.

Since gold nanoparticles have surfaces that may hold modular bits, the researchers can effectively build customized assemblies by simply mixing building blocks, according to paper co-author Kanna Mori, a graduate student in the Department of Biotechnology and Life Science in TUAT.

“Photoaffinity probes can be readily obtained in the probe precursors, preassembled with three types of building blocks — each containing a clickable group, a photoreactive group and a water-soluble spacer group–and then rapidly incorporate a small-molecule of curiosity via’click chemistry,'” Mori said.

The fabricated small molecule, even after being conjugated to the nanoparticle, acts as a parent molecule which would naturally bind to a protein, and the photoreactive group reacts to ultraviolet light irradiation that triggers the probe. Once activated, the research can capture and isolate a target protein.

“We demonstrated that clickable photoaffinity probe precursors will offer a rapid access to photoaffinity probes of different kinds of bioactive small molecules to identify their target proteins,” Sakurai said.

Next, the researchers plan to explore the usefulness of gold-nanoparticle probes in goal identification studies in live cells, expanding their work to factor in physiological conditions. They also plan to introduce complex natural products and some pharmaceuticals into the gold-nanoparticles to start identifying their unknown target proteins.