Abstract
Monkeypox virus (MPXV) caused the 2022-2023 global mpox and the concurrent outbreaks in Africa, disproportionately affecting immunocompromised individuals such as people living with HIV. With no approved treatment available, we developed a robust artificial intelligence (AI) pipeline for discovering broad-spectrum poxvirus inhibitors that target the viral DNA polymerases. Among the identified leading candidates, we found that the clinically used antiretroviral drugs bictegravir and etravirine potently inhibit MPXV clade Ia, Ib and IIb infections in human intestinal and skin organoids. The broad anti-poxvirus activities of bictegravir and etravirine were further demonstrated against infections of other Orthopoxviruses such as vaccinia virus and cowpox virus. These findings support the repurposing of bictegravir and etravirine for treating mpox, especially for patients co-infected with HIV, warranting follow-up clinical investigation. The established AI pipeline and our antiviral drug discovery strategies bear major implications for responding to the ongoing mpox emergency and preparing for future poxvirus epidemics.