Researchers Develop Peptoid-Based Materials Mimicking Nature's Precise Shapes

Researchers at Pacific Northwest National Laboratory developed peptoid-based materials that mimic nature's precise molecular shapes, controlling their handedness and shape. The breakthrough could lead to more effective treatments, diagnostic tools, and insights into protein folding-related diseases like Alzheimer's.

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Researchers Develop Peptoid-Based Materials Mimicking Nature's Precise Shapes

Researchers Develop Peptoid-Based Materials Mimicking Nature's Precise Shapes

A team of researchers led by materials scientist Chun-Long Chen at Pacific Northwest National Laboratory (PNNL) has developed peptoid-based materials that can mimic nature's precise molecular shapes, controlling their handedness and shape to create potential applications in drug delivery, diagnostics, and therapeutics. Proteins in nature assemble into well-defined shapes that grant them their function, and understanding how they assemble and the origins of their particular shape could be significant for various applications.

Why this matters: This breakthrough in peptoid-based materials could lead to the development of more effective and targeted treatments for diseases, as well as improved diagnostic tools. Moreover, understanding the precise shapes and handedness of molecules could unlock new avenues for research intoprotein folding-related diseases, such as Alzheimer's.

Chen's team aimed to control these shapes by creating peptoid-based materials inspired by nature. They designed peptoid assemblies with precise shapes, directing the"handedness"of the helix, which is crucial in designing specialized molecules like medications. The team discovered a way to control the handedness of a peptoid helix by manipulating the sequence of the peptoid side chains.

The researchers successfully developed a three-dimensional helical nanostructure, observing that the inclusion of special "functional groups" of atoms in their peptoid sequences allowed them to create structures with special functions, similar to protein assemblies. "Peptoids have the potential to be used in a variety of applications. Based on their assembled shapes and other properties, it's possible to design peptoids as drug delivery agents or artificial enzymes," said Chun-Long Chen.

Chen emphasized the importance of handedness in designing specialized molecules: "Handedness is extremely important when designing specialized molecules, like medications. Understanding and controlling this handedness can provide insights into processes like protein assembly and could be valuable to finding cures to protein folding-related diseases such as Alzheimer's disease." While this is a fundamental study, Chen noted that the research provides additional insights into creating better, more precise materials—like those found in nature—for specific applications.

The researchers drew inspiration from hematophagous organisms, such as leeches, ticks, and mosquitoes, which use potent inhibitors of the coagulation proteases to acquire blood meals. These inhibitors are frequently peptides that engage the target protease through exosite and active site interactions, achieving high potency and rapid onset of action during feeding.

Building on this inspiration, the team created several EXACT (EXosite and ACTive site) inhibitors targeting thrombin and factor Xa de novo by linking EXosite binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor synergizes with and enhances the potency of small molecule active site inhibitors by many hundred fold, can redirect an active site inhibitor's selectivity towards a different protease, and enable efficient reversal of inhibition by an antidote that disrupts bivalent binding.

One EXACT inhibitor, HD22-7A-DAB, demonstrated extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid-onset anticoagulant to support cardiovascular surgeries. The researchers believe this generalizable molecular engineering strategy can be used to create selective, potent, and rapidly reversible EXACT inhibitors against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.

Chen and his team hope to create a wide range of peptoid-based nanomaterials for applications, with controlling peptoid shape being just the first step. This research provides a foundation for developing precise, nature-inspired materials with potential applications spanning drug delivery, diagnostics, and therapeutics.