Biomolecular condensates could transform drug discovery, says Dewpoint Therapeutics

By Greg Slabodkin, ScienceBoard Editor in Chief

August 19, 2022 -- Boston-based biotech company Dewpoint Therapeutics contends there are untapped opportunities for targeting biomolecular condensates to develop therapeutic agents for a wide array of diseases, potentially transforming the drug discovery process.

Writing in a perspective piece this week in the journal Nature Reviews Drug Discovery, the company's scientists made their case that a vast range of conditions have pathways that are regulated by condensates or arise from the dysfunction of condensates.

Condensates are membraneless organelles that form dynamically throughout the cell via a process called phase separation. Their behavior is governed by the concentrations of, and multivalent interactions between, proteins and nucleic acids.

These subcellular compartments organize and concentrate molecules within cells, enabling key biochemical processes and driving various diseases, including neurodegeneration, cancer, cardiomyopathy, and viral infection.

"Emerging understanding of condensate function in normal and aberrant cellular states, and of the mechanisms of condensate formation, is providing new insights into human disease and revealing novel therapeutic opportunities," the authors wrote. "We propose that such insights could enable a previously unexplored drug discovery approach based on identifying condensate-modifying therapeutics (c-mods), and we discuss the strategies, techniques, and challenges involved."

While traditional drug discovery focuses on modifying the function of a single target biomolecule, the authors argue that by reimagining the drug target as the molecular community that resides within a condensate researchers can modify the function of biological pathways and biomolecules that were previously considered "undruggable" -- and by targeting a disease node, a single therapeutic agent might help treat a larger patient population.

At the same time, the authors acknowledge a myriad of challenges due to the complex nature of condensates and the forces that lead to condensate formation. Still, they believe the high complexity and dynamic nature of condensates raise both unique challenges and opportunities for c-mod discovery.

"Many questions and challenges are topics of active investigation by the community," according to the authors. "For example, how do we demonstrate causality between disease and condensatopathies? How do we identify 'hub' condensatopathies for polygenic diseases? What are the different signalling and regulatory pathways that are dysregulated via any one target condensate? What are the most informative components for understanding the function of the condensate and the effects of c-mods?"

Dewpoint Therapeutics claims to be the first company to apply the emerging understanding of biomolecular condensates to drug discovery, entering the field in 2018. However, other biotech companies such as Faze Medicines, Nereid Therapeutics, and Transition Bio have entered the space in the last couple of years.

Nonetheless, corresponding author Dr. Isaac Klein, PhD, chief scientific officer at Dewpoint Therapeutics, said in a statement that to the company's knowledge "this is the first time that a cohesive logic has been assembled outlining how a deep understanding of condensate biology can revolutionize the drug discovery process across therapeutic areas."

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