Development of Lipopeptides as Orthoflavivirin Inhibitors with Low Micromolar Broad-Spectrum Antiorthoflaviviral Activity.

ABSTRACT: Orthoflaviviral infections increasingly impact the global population; no specific therapeutic treatments are available. The orthoflaviviral protease NS2B-NS3 is a promising target for antiviral drug development. Here, we present the design, synthesis, structure-activity relationship (SAR), and in vivo PK study of a novel lipopeptide scaffold emerging from exploration of the previously investigated polycationic geminoids 4-6. The N-palmitoyl moiety is essential for protease inhibition; optimization of the peptide sequence led to lipopeptides 73 and 79, which selectively inhibited dengue virus (DENV2) NS2B-NS3 and exhibited low micromolar antiviral potency in DENV2-, West Nile virus (WNV)-, and Zika virus (ZIKV)-infected cells without significant cytotoxicity. Com

SUBMITTER: Cavina L 

PROVIDER: S-EPMC12621197 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature