Mar 17 2015
Researchers from the Howard Hughes Medical Institute (HHMI) have synthesised small molecules using a simple technique, thus removing a key hurdle that restricted the investigation of a class of compounds providing great potential in the field of medicine and technology.
The research team headed by Martin Burke, used a single automated method for the synthesis of 14 different groups of small molecules from a universal set of building blocks. They plan to expand the method to enable the fabrication of a number of molecules with useful prospects using a single machine, which they termed as a '3D printer' suited for small molecules.
Burke states that the extremely customized method which chemists have been using continuously for the synthesis of small molecules is not only time consuming but also unreachable for most researchers.
"A lot of great medicines have not been discovered yet because of this synthesis bottleneck," he says. With his new technology, Burke aims to change that. "The vision is that anybody could go to a website, pick the building blocks they want, instruct their assembly through the web, and the small molecules would get synthesized and shipped," Burke says.
"We're not there yet, but we now have an actionable roadmap toward on-demand small-molecule synthesis for non-specialists."
A large number of small molecules are created by nature, and a large number of them have been adapted by researchers for useful applications. Many of the popular drugs are believed to be small molecules. Likewise so are several of the essential biological research instruments. Additionally, a broad range of technologies such as LEDs, solar cells, and diagnostic instruments depend upon small molecules.
"Small molecules have already had a big impact on the world," says Burke. "But we've barely touched the surface of what they're capable of achieving. In large part, that's because there's a major synthesis bottleneck that precludes accessing all of their functional potential."
Burke states that chemists normally approach the manufacture of small molecules in a customized manner by designing numerous chemical reactions which when applied to appropriate starting materials will produce the desired result.
"Every time you make a molecule you have to develop a unique strategy. That customization is slow," he says. Furthermore, it requires expertise. "Currently you have to have a high degree of training in synthesis to make small molecules," Burke says.
Burke has been involved in exploring ways to treat disease using small molecules. Animals, plants and microbes produce a lot of small molecules with protein-like functions, and with some accurate chemical modifications. Burke believes that some of these natural products can be optimized to imitate the functioning of missing proteins sufficient to improve the health of a patient.
However to achieve this feat, his team will have to synthesize and examine not only the small molecule available in nature, but also study new forms with targeted alterations. Creating those molecules is likely to be a major challenge to drug discovery, Burke says. "Doing real atomistic modifications to transform nature's starting points into actual medicines is really, really challenging. The slow step in most cases in the synthesis. As a result, many natural products don't get worked on in any practical way."
The HHMI team gathered clues from nature to fine-tune the synthesis process of the molecules they were studying, thereby building a method which has been presently expanded to make it more universal. "Nature makes most small molecules the same way," Burke says. "There are a small number of building blocks that are coupled together over and over again, using the same kind of chemistry in an iterative fashion." That indicates the naturally modular form of the small molecules. Therefore when the research team tested the chemical structures of many different natural products, a clear pattern materialized.
"There are building blocks that appear over and over again, and we've been able to dissect out the building blocks that are most common," he says. The small-molecule synthesizer constructed by the team took these building blocks, each of which had two chemical connectors which could be easily connected to the next part on a different building block and snapped them together similar to pop beads using a basic chemical reaction.
14 different small molecules were synthesized by the team using this technique. The molecules ranged from comparatively straightforward linear structures to compactly folded molecules with many chemical rings. They built several hundred of these chemical building blocks and supplied them commercially.
"But it's not really about the numbers," he says. "We are showing that with a very reasonable number of building blocks we can make many different types of natural products."
Burke explained how their new technology is available for use to synthesize a range of highly complex natural products, which means that the atom-by-atom variations needed by researchers to optimize these molecules into therapeutic compounds or technological tools are now readily available.
Burke has founded a company, REVOLUTION Medicines where this technology is going to further explored and developed.
Eventually Burke states that he is keen on empowering non-specialists including medical doctors, scientists, engineers, and even the public - to fabricate small molecules.
"When you put the power to manufacture into the hands of everyone, history speaks toward tremendous impact," he says. "A 3D printer for molecules could allow us to harness all the creativity, innovation, and outside-the-box thinking that comes when non-experts start to use technology that used to only be in the hands of a select few."
Their research findings are published in the March 13, 2015, issue of the journal Science.