Targeting the 5-HT7 receptor to block influenza virus entry: mechanistic insights and therapeutic potential of SB269970 HCl.

Influenza viruses persist as a significant global health challenge, with the emergence of drug-resistant strains limiting the effectiveness of current antiviral treatments. Inhibiting the early stages of viral replication is known to reduce virus-induced cytopathic effects; however, few therapeutics target these stages or the host factors supporting them, creating a critical gap in anti-influenza strategies development. This study aimed to address this gap by evaluating the antiviral potential of SB269970 HCl, a 5-HT7 receptor antagonist, against influenza viruses. We tested the efficacy of the compound using in vitro models (with multiple influenza strains) and an in vivo murine model of lethal influenza infection. In vitro, SB269970 HCl effectively suppressed viral replication, and in vivo, it significantly improved survival rates and reduced the viral load in infected mice. Mechanistic experiments revealed that SB269970 HCl exerts its antiviral activity by blocking endocytosis of the influenza virus, a key step in the viral life cycle. Genetic knockdown of the 5-HT7 receptor inhibited viral entry, demonstrating the pivotal role of this receptor in facilitating viral internalization. These findings advance anti-influenza research by identifying the 5-HT7 receptor and its associated pathways as novel druggable targets. Unlike traditional antivirals, which are prone to resistance, SB269970 HCl targets host factors, offering a broad-spectrum strategy effective against diverse influenza strains, and establishing it as a promising candidate for further antiviral development.