Biomolecular Condensates Might Revolutionize Drug Discovery

Researchers from Dewpoint Therapeutics published a paper “Modulating biomolecular condensates: a novel approach to drug discovery” in Nature Reviews Drug Discovery that examines the potential of biomolecular condensates to transform drug discovery. Condensates are membrane-less organelles that form dynamically throughout the cell via phase separation.

Over the last decade scientists have paid increasing attention to the role of biomolecular condensates in cellular organization and disease, according to a company spokesperson, who adds that the Dewpoint authors discuss the untapped opportunities for targeting biomolecular condensates to develop therapeutic agents for various diseases.

“To our 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,” says Isaac Klein, MD, PhD, CSP at Dewpoint Therapeutics and corresponding author.

“In the past decade, membraneless assemblies known as biomolecular condensates have been reported to play key roles in many cellular functions by compartmentalizing specific proteins and nucleic acids in subcellular environments with distinct properties. Furthermore, growing evidence supports the view that biomolecular condensates often form by phase separation, in which a single-phase system demixes into a two-phase system consisting of a condensed phase and a dilute phase of particular biomolecules,” write the investigators.

“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. In this perspective, 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.”

Condensate dysregulation as potential node of disease origination

The authors propose that condensate dysregulation may represent a node of disease origination in patients with different genetic background and environmental exposures, and that these nodes can be leveraged as drug targets. Classical drug discovery focuses on modifying the function of a single target biomolecule, they note.

The journal article summarizes the rules that underlie the formation, dissolution, and regulation, of biomolecular condensates, which have emerged in the last decade. Based on these rules, the authors discuss how condensate dysfunction drives various diseases, including neurodegeneration, cancer, cardiomyopathy, and viral infection.

By reimagining the drug target as the “molecular community,” which resides within a condensate, researchers say they can modify the function of biological pathways and biomolecules that were previously considered undruggable.

Another promising aspect of condensate drug discovery is that by targeting a disease node, a single therapeutic agent might help treat a larger patient population.

“Condensates are unlike anything seen before in drug discovery. Dewpoint is leading the understanding of condensates and the diverse ways new medicines could be developed to restore aberrant condensate function. No one has previously published the potential of biomolecular condensates from a drug discovery perspective, and Dewpoint scientists are bringing forward a groundbreaking perspective to the field,” comments Mark Murcko, PhD, therapeutics board and scientific advisory board member at Dewpoint Therapeutics and co-corresponding author.

“Dewpoint has developed a platform and drug discovery pipeline that exploits cutting-edge technology and a deep understanding of condensate biology to discover novel condensate modifiers, or c-mods,” adds Klein. “These molecules have the ability to tackle the root cause of complex diseases and address previously undruggable targets.”