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It has implications in cellular physiology and disease conditions like cancer and neurodegenerative disorders. Many proteins associated with neurodegenerative disorders like RNA binding protein FUS (FUsed in Sarcoma), alpha\u2010synuclein (\u03b1\u2010Syn), TAR DNA binding protein 43 (TDP\u201043), and tau are shown to undergo LLPS. Recently, the tau protein responsible for Alzheimer's disease (AD) and other tauopathies is shown to phase separate into condensates <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. The diverse noncovalent interactions among the biomolecules dictate the complex LLPS phenomenon. There are limited chemical tools to modulate protein LLPS which has therapeutic potential for neurodegenerative disorders. We have rationally designed cyclic dipeptide (CDP)\u2010based small\u2010molecule modulators (SMMs) by integrating multiple chemical groups that offer diverse chemical interactions to modulate tau LLPS. Among them, compound <jats:bold>1c<\/jats:bold> effectively inhibits and dissolves Zn\u2010mediated tau LLPS condensates. The SMM also inhibits tau condensate\u2010to\u2010fibril transition (tau aggregation through LLPS). This approach of designing SMMs of LLPS establishes a novel platform that has potential implication for the development of therapeutics for neurodegenerative disorders.<\/jats:p>","DOI":"10.1002\/psc.3465","type":"journal-article","created":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T05:29:01Z","timestamp":1670304541000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Cyclic dipeptide\u2010based small molecules modulate zinc\u2010mediated liquid\u2013liquid phase separation of tau"],"prefix":"10.1002","volume":"29","author":[{"given":"Madhu","family":"Ramesh","sequence":"first","affiliation":[{"name":"Bioorganic Chemistry Laboratory, New Chemistry Unit Jawaharlal Nehru Centre for Advanced Scientific Research  Bengaluru India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenikkayala","family":"Balachandra","sequence":"additional","affiliation":[{"name":"Bioorganic Chemistry Laboratory, 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