Novel Synthetic Biomolecule Degrades Disease-Related Proteins

Northwestern Medicine scientists have developed a novel synthetic biomolecular condensate that can degrade intracellular disease-causing proteins, providing a framework for new therapeutic approaches for a wide range of diseases, as detailed in a recent study published in Nature Communications.

Shana Kelley, PhD, the Neena B. Schwartz Professor of Chemistry, Biomedical Engineering, and Biochemistry and Molecular Genetics and the president of the Chan Zuckerberg Biohub Chicago, was senior author of the study.

Targeted protein degradation is an emerging therapeutic strategy that harnesses cells’ own degradation machinery to clear disease-causing proteins. However, achieving this degradation process across different cell types has remained a challenge due to subtle variations in protein structure.

In the current study, the scientists developed a synthetic biomolecular condensate as a protein degradation tool to deliver targeted antibodies to KRAS, a well-known oncogenic protein.

Biomolecular condensates are highly dynamic, membrane-less structures in cells that concentrate proteins and nucleic acids and are involved in many cellular processes, including RNA metabolism and DNA damage response.

Compared to conventional synthetic carriers, the new biomolecular condensate incorporates a short proteasome-targeting motif into phase-separation precursors, preserves antibody activity, enables direct proteasome recruitment and improves delivery uniformity.

When combined with a KRAS mutation-specific antibody in heterozygous cells, the scientists found that their biomolecular condensate selectively degraded the KRAS G12V mutation without affecting wild-type phenotypes.

“There’s only one amino acid change between the wild-type and the disease-causing phenotype, and that’s why we used the antibody to recognize which is which,” said Yi Li, a graduate student in Biomedical Engineering at the McCormick School of Engineering and lead author of the study.

Additionally, the scientists found their approach also suppressed tumor growth in a KRAS G12V mutation mouse model.

“Given the widespread availability and diversity of antibodies, we believe IgG-biomolecular condensate holds strong potential as a broadly applicable targeted protein degradation modality for targeting a wide array of intracellular disease-related proteins,” the authors wrote.

As for next steps, the scientists aim to better understand the potential of bimolecular condensates as a new category of cytomemetic nanomaterials, according to Yi.

“In the cell biology field, we know how cells create and allocate membrane-less organelles. However, how cells interact with artificial biomolecular condensates is largely unknown. Our upcoming work is trying to understand the principles governing condensate–cell interactions and to leverage these insights to engineer therapeutic condensates that function beyond drug delivery; they can perform cell-like tasks after internalization, such as targeted protein disposal, molecular sequestration, and intracellular cargo reallocation. Biomolecular condensates may represent a new class of programmable biomaterials,” Li said.

This work was supported by the Ryan Family Research Acceleration Fund, the IIN Willens Center for Nano Oncology and the IIN Ryan fellowship.