Bioactive macrocycles: NMR structures

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  • Published: Jun 1, 2016
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Bioactive macrocycles: NMR structures

Time for TEA

Partial rotating-frame Overhauser effect spectrum of MC1 showing the EXSY off-diagonal peaks. Credit: Nature Chem/Alabi et al)

Bioactive peptidomimetic macrocycles have been developed by a group of scientists at Cornell University in Ithaca, New York, USA, and studied using nuclear magnetic resonance (NMR) spectroscopy. Mintu Porel, Dana Thornlow, Ngoc Phan and Christopher Alabi report details in the journal Nature Chemistry. The compounds might lead the way to an entirely new class of antibiotics or drug delivery systems.

Alabi, who is an assistant professor in the Robert Frederick Smith School of Chemical and Biomolecular Engineering, led the study, using his team's expertise in biomimetics and focusing on how they can use specific sequences and molecular composition to induce macromolecular assembly, control chain dynamics and so design particular chemical and biological properties into their compounds.

"I think we've made significant progress," Alabi explains. "I think the overall goal is not to recreate biological molecules – the goal is to maybe capture some of the functions of what we want, in the smallest sequence that we can make." The bioactive macrocyclic compounds the team has synthesized using a one-pot acid-catalysed cascade reaction as a proof of principle are known as oligothioetheramides (oligoTEAs). They were able to replicate the synthesis more than 20 times to make variations on the basic theme, revealing the simplicity and versatility of the process. "We were looking to make something with simple chemistry, that anyone can make," Porel adds. "It's very versatile in that way." The team's structural NMR work on these compounds revealed the presence of conformational isomers, and they could then exploit that information to determine the local chain dynamics within the macromolecular structure.

Knotted pearl necklace

The macrocycle, resembling a pearl necklace in some ways can be made large or smaller by placing a "knot" somewhere in the chain. "We can essentially tie these strings into different structures," Alabi explains. "If you take two pearls on a string and you want to fold just these two pearls together, you have to put functionalities on them that would allow the reaction you're looking for to take place."

It is that word "bioactive" that makes these novel compounds particularly intriguing. Compounds have to be biocompatible and simple to put together to be useful. "The functionalities that you’re including are specific to a target biological application...It refocuses the project to something that, in the long term, is commercially viable and biologically relevant," Alabi adds. Early tests on macrocyclic oligoTEAs reveal them to have potent antibacterial activity although it is still a long way off before such compound would ever enter clinical testing and become available as antibiotic drugs.

Fancy molecules

Bioactivity does not necessarily hinge on the number of building blocks, having precise control of the sequence could be more important and allow a bioactive substance to be constructed without superfluous units that are perhaps present in a natural structure for past evolutionary reasons or other functionality that is not central to the target activity being sought by the scientists.

"We're just scratching the surface," Alabi says. "Biological molecules fold into myriad structures, so we're taking baby steps and trying to understand the role of composition and structure on molecular function." But, for now, that will suffice. To produce a drug, the process has to be relatively simple and not expensive otherwise commercial concerns precluded its viable manufacture irrespective of how important a specific drug might be to human health. "To make this into a drug, it has to be simple and it has to be cheap," Alabi explains. "It has to be scalable – you have to be able to make drums of it. And that’s what we keep in the forefront. Otherwise, it's just a really fancy molecule that'll be limited to laboratory studies."

"The next step involves creating new information coded linear and folded macromolecules to study the relationship between oligoTEA structure and biological activity (antibacterial, cellular internalization and drug delivery)," Alabi told SpectroscopyNOW.

Related Links

Nature Chem 2016, 8, 590-596: "Sequence-defined bioactive macrocycles via an acid-catalysed cascade reaction"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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