Biomolecular condensates: new opportunities for drug discovery and RNA therapeutics. 2022

Brooke A Conti, and Mariano Oppikofer
Pfizer Centers for Therapeutic Innovation, Pfizer Inc., New York, NY, USA.

Biomolecular condensates organize cellular functions in the absence of membranes. These membraneless organelles can form through liquid-liquid phase separation coalescing RNA and proteins into well-defined, yet dynamic, structures distinct from the surrounding cellular milieu. Numerous physiological and disease-causing processes link to biomolecular condensates, which could impact drug discovery in several ways. First, disruption of pathological condensates seeded by mutated proteins or RNAs may provide new opportunities to treat disease. Second, condensates may be leveraged to tackle difficult-to-drug targets lacking binding pockets whose function depends on phase separation. Third, condensate-resident small molecules and RNA therapeutics may display unexpected pharmacology. We discuss the potential impact of phase separation on drug discovery and RNA therapeutics, leveraging concrete examples, towards novel clinical opportunities.

UI MeSH Term Description Entries
D011506 Proteins Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein. Gene Products, Protein,Gene Proteins,Protein,Protein Gene Products,Proteins, Gene
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000091582 Biomolecular Condensates Membraneless intracellular compartments formed through liquid-liquid phase separation from the surrounding CYTOPLASM or nucleoplasm or by the concentration of proteins and nucleic acids into droplets as they aggregate on static cellular structures such as CELL MEMBRANES. Examples include CELL NUCLEOLI; STRESS GRANULES; PARASPECKLES; HISTONE LOCUS BODIES; and POSTSYNAPTIC DENSITIES. Membraneless Organelles,Biomolecular Condensate,Condensate, Biomolecular,Condensates, Biomolecular,Membraneless Organelle,Organelle, Membraneless,Organelles, Membraneless
D012313 RNA A polynucleotide consisting essentially of chains with a repeating backbone of phosphate and ribose units to which nitrogenous bases are attached. RNA is unique among biological macromolecules in that it can encode genetic information, serve as an abundant structural component of cells, and also possesses catalytic activity. (Rieger et al., Glossary of Genetics: Classical and Molecular, 5th ed) RNA, Non-Polyadenylated,Ribonucleic Acid,Gene Products, RNA,Non-Polyadenylated RNA,Acid, Ribonucleic,Non Polyadenylated RNA,RNA Gene Products,RNA, Non Polyadenylated
D015388 Organelles Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the MITOCHONDRIA; the GOLGI APPARATUS; ENDOPLASMIC RETICULUM; LYSOSOMES; PLASTIDS; and VACUOLES. Organelle
D055808 Drug Discovery The process of finding chemicals for potential therapeutic use. Drug Prospecting,Discovery, Drug,Prospecting, Drug

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