Phosphaphenalene Gold(I) Complexes as Broad-Spectrum Antivirals Against Emerging Flaviruses

Flaviviruses are emerging and re-emerging pathogens of major global health concern that can replicate in hosts of different phyla, including humans. Among them, Zika virus (ZIKV) is associated with severe neurological outcomes, including neonatal microcephaly, congenital malformations, and Guillain-Barre syndrome in adults. Usutu virus (USUV), another mosquito-borne flavivirus, primarily infects birds and has been linked to neurological symptoms in humans. Bagaza virus (BAGV) significantly affects the wildlife of some bird species and carries a noteworthy risk of zoonotic transmission. Despite their clinical significance, approved antiviral options for flaviviral infections (including ZIKV, USUV, and BAGV) are not available, and current management focuses primarily on providing symptomatic relief and supportive care. To address this therapeutic gap, we evaluated the antiviral activity of five phosphaphenalene-based gold (I) complexes. These phosphaphenalene-derived compounds exhibit straightforward and versatile chemistry, allowing access to derivatives with improved stability, bioactivity, selectivity, and cytotoxicity, thereby enhancing their biological activities. Two compounds showed potent inhibition of ZIKV, USUV, and BAGV replication at low micromolar concentrations, with ZIKV displaying greater sensitivity. ZIKV titers were reduced by up to three orders of magnitude in a dose-dependent fashion. Mechanistic studies revealed that both compounds inhibited thioredoxin reductase and disrupted autophagy. This study represents the first demonstration of the potential of phosphaphenalene-based gold (I) complexes as promising candidates against flavivirus infections, offering a promising foundation for the development of urgently needed antiviral therapies with potential impact on global health.