The cytoplasmic human Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3 or A3) cytidine deaminases G and F (A3G and A3F) can block the spread of human immunodeficiency virus (HIV). HIV counteracts this cell-intrinsic defense through a viral protein called viral infectivity factor (Vif). Vif causes proteasomal degradation of A3G and A3F proteins (A3G/F) in HIV-producing cells to ensure infectivity of virions subsequently released from these cells. Here, we optimized a lead compound reported previously to boost cellular levels of A3G. The modified analogs designed, synthesized, and evaluated here inhibit cell-mediated post-translational degradation of A3G/F, whether Vif is present or not. This increases A3G/F incorporation into Vif-positive virions to decrease viral infectivity. The compounds and processes described here can facilitate the development of new anti-HIV therapeutics whose host-targeted effect may not be evaded by resistance-conferring mutations in HIV Vif.

In 2017, the pharmaceutical company Eli Lilly announced it would stop manufacturing quinidine, the only Food and Drug Administration–approved treatment for severe malaria in the United States at the time. This decision left critically ill patients and their providers without access to the standard of care and created dangerous delays in obtaining life-saving therapy. As providing access to essential medications and minimizing preventable harm are fundamental aspects of ethical healthcare, Eli Lilly's action effectively prevented the delivery of ethical care to patients across the country. This case raises urgent and essential questions regarding the ethical obligations of a for-profit company when faced with conflicting interests and the ability of the broader healthcare community—including government agencies, hospital systems, and professional societies—to safeguard ethical patient care. We examined how the absence of enforceable accountability and oversight throughout the healthcare system allowed the actions of a single corporate entity to undermine the system's ethics without opposition. We propose interventions including amended production contracts, expedited regulatory approval of essential therapies, and the development of multidisciplinary advisory bodies to promote and protect the delivery of ethical care. As such conflicts will inevitably recur, proactive, collaborative, and enforceable mechanisms that center ethical patient care are urgently needed.