A medicinal chemistry overview of direct-acting antivirals approved in 2013–2024 by US FDA

Remarkable progress in understanding molecular, cellular and structural viral biology over the last ten years has paved the way for a prosperous age of antivirals. The U.S. FDA has approved 27 new direct-acting antivirals (DAAs), marking a clear step forward compared to the previous 50 years (from 1962, when the first DAA was introduced into therapy, to 2012). Antiviral agents have been shown to play a crucial role in modern medicine, fighting infections, reducing disease severity and preventing viral spread. Their importance has been underscored during numerous global health crises affecting humans over the centuries. In this review, we provide a comprehensive analysis of the 27 newer FDA-approved DAAs, from discovery to final approval. We focus particularly on medicinal chemistry, covering design, optimization, mechanisms of action and co-crystallographic/Cryo-EM structures. In the final section, we provide a detailed discussion of the achievements made during the period under review. Additionally, given that the current antiviral arsenal is characterized by numerous limitations and is solely effective against a small number of viruses, leaving many others without effective treatment, an overview of innovative approaches and targets that could potentially address unmet clinical needs was also provided.