Phenotypic identification of fragments as antivirals

Konaklieva, Monika I and Lutz, Alex and Plotkin, Balbina J (2025) Phenotypic identification of fragments as antivirals. World Journal of Biology Pharmacy and Health Sciences, 22 (2). pp. 301-313. ISSN 2582-5542

While fragment-based drug discovery (FBDD), i.e., target-based approach, continues to produce candidates for research directed at drug discovery and chemical biology, a strategy increasingly being adopted is phenotypic screening, also referred to as Phenotypic Drug Discovery (PDD). Among the many therapies currently being explored, synthetic small-molecule drugs represent a prime opportunity for bringing treatments to the marketplace to meet the rising global demand for antivirals. Newer targets for antivirals are critical metabolic pathways in host cells, which viruses are known to hijack to support their replication and continued survival. Using standard synthetic techniques, a library (~50 compounds) of low molecular weight urea and amide chemotypes was developed to target virus entry. The library is based on the fragment-to-lead approach, utilizing phenotypic screen whole cell screens. The fragments based on the urea scaffold with nitrogen heterocycle, e.g., pyrimidine moiety, and the trifluoromethyl-containing amides demonstrated activity against respiratory viruses such as influenza viruses, enterovirus, and respiratory syncytial virus. These preliminary results serve as a foundation for optimizing our current fragment library to increase the potency of the next generation of compounds and to define their potential as antivirals.