Advancing Small Molecule Drug Discovery by Targeting Biomolecular Condensates and Evaluating Novel Chemical Scaffolds

Abstract

Small molecule drugs comprise nearly 90% of global drug sales. However, existing small molecules have struggled to treat complex disease landscapes such as those found in neurodegenerative diseases, emerging viral outbreaks, and evolving drug resistance. A promising approach to develop treatments for these unmet medical needs is to discover new small molecules by combining improved target selection with novel drug modalities. In Chapter 1 of this thesis, I describe the identification of small molecule modulators of SARS-CoV-2 nucleocapsid (N) protein condensation. These compounds exhibit pan-human coronaviral N condensation modulatory activity – an early but crucial demonstration that targeting viral condensation can be a viable means to achieve antiviral efficacy. In Chapter 2, I describe the development of two alternative high throughput screening assays that robustly report on changes in protein condensation states in response to small molecule condensate modulators, expanding the toolkit available for future condensate modulator screening campaigns. Finally, in Chapter 3, I detail the discovery of potent cellular uptake inhibitory activity exhibited by several groups of plant polyphenols, highlighting how their bioactivity is related to certain chemical moieties typically under-represented in small molecule drug discovery. Altogether, this thesis demonstrates the feasibility of targeting “undruggable” condensates and exploiting unique chemical moieties for potential therapeutic outcomes, challenging the boundaries of modern drug discovery.